U.S. patent number 8,846,694 [Application Number 12/996,786] was granted by the patent office on 2014-09-30 for pyrrolidone derivatives for use as metap-2 inhibitors.
This patent grant is currently assigned to Merck Patent GmbH. The grantee listed for this patent is Holger Enderle, Timo Heinrich, Alfred Jonczyk, Thorsten Knoechel, Mireille Krier, Frank Zenke. Invention is credited to Holger Enderle, Timo Heinrich, Alfred Jonczyk, Thorsten Knoechel, Mireille Krier, Frank Zenke.
United States Patent |
8,846,694 |
Heinrich , et al. |
September 30, 2014 |
Pyrrolidone derivatives for use as MetAP-2 inhibitors
Abstract
Compounds of the formula (I), in which R, X, Y, Z, R.sup.3 and
R.sup.4 have the meanings indicated in claim 1, are inhibitors of
methionine aminopeptidase and can be employed for the treatment of
tumours. ##STR00001##
Inventors: |
Heinrich; Timo (Gross-Umstadt,
DE), Krier; Mireille (Darmstadt, DE),
Knoechel; Thorsten (Darmstadt, DE), Jonczyk;
Alfred (Darmstadt, DE), Zenke; Frank (Darmstadt,
DE), Enderle; Holger (Ockenheim, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Heinrich; Timo
Krier; Mireille
Knoechel; Thorsten
Jonczyk; Alfred
Zenke; Frank
Enderle; Holger |
Gross-Umstadt
Darmstadt
Darmstadt
Darmstadt
Darmstadt
Ockenheim |
N/A
N/A
N/A
N/A
N/A
N/A |
DE
DE
DE
DE
DE
DE |
|
|
Assignee: |
Merck Patent GmbH (Darmstadt,
DE)
|
Family
ID: |
41317641 |
Appl.
No.: |
12/996,786 |
Filed: |
May 13, 2009 |
PCT
Filed: |
May 13, 2009 |
PCT No.: |
PCT/EP2009/003400 |
371(c)(1),(2),(4) Date: |
March 28, 2011 |
PCT
Pub. No.: |
WO2010/003475 |
PCT
Pub. Date: |
January 14, 2010 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20110263561 A1 |
Oct 27, 2011 |
|
Foreign Application Priority Data
|
|
|
|
|
Jun 10, 2008 [DE] |
|
|
10 2008 027 574 |
|
Current U.S.
Class: |
514/263.2;
544/277 |
Current CPC
Class: |
A61P
17/06 (20180101); A61P 27/02 (20180101); A61K
9/0019 (20130101); A61K 9/0048 (20130101); A61P
3/10 (20180101); A61P 9/10 (20180101); A61K
9/2018 (20130101); A61P 35/00 (20180101); A61P
19/02 (20180101); A61P 19/10 (20180101); C07D
473/34 (20130101); A61P 43/00 (20180101); A61K
9/02 (20130101); A61P 35/04 (20180101); C07D
513/04 (20130101); A61K 9/19 (20130101); A61P
35/02 (20180101); A61P 3/04 (20180101); C07D
487/04 (20130101); C07D 471/04 (20130101) |
Current International
Class: |
A61K
31/52 (20060101); C07D 403/04 (20060101) |
Field of
Search: |
;544/277,280
;514/263.2 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Wermuth, Camille G. Molecular Variations Based on Isoteric
Replacements. The Practice of Medicinal Chemistry. Academic Press,
1996. pp. 203-237. cited by examiner .
Selvakumar, Ponniah. Biochimica et biophysics Acta 1765
(2006)148-154. cited by examiner .
Bradshaw, Ralph. Expert Opin. Ther. Patehts (2004) 14(1): 1-16.
cited by examiner .
MedicineNet.com <http://www.medterms.com>, 2004. cited by
examiner .
WORLP IP Organization. "International Search Report."
PCT/EP2009/003400, Applicant: Merck Patent GmbH, Mailed Feb. 23,
2010. cited by applicant.
|
Primary Examiner: Shameem; Golam M M
Assistant Examiner: Daniel; Laura
Attorney, Agent or Firm: Millen, White, Zelano &
Branigan, P.C.
Claims
The invention claimed is:
1. A compound that is TABLE-US-00004 Com- pound No. Name and/or
structure "A1"
6-[(R)-2-(Naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A2"
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-
ylmethoxy]naphthalene-1-carbaldehyde "A3"
6-[(R)-2-(4-Morpholin-4-ylmethylnaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine "A4"
6-[(R)-2-(4-Butoxymethylnaphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A6"
Morpholin-4-yl(4-{2-[1-(9H-purin-6-yl)pyrrolidin-2-yl]-
ethyl}naphthalen-1-yl)methanone "A8"
6-[(R)-4,4-Difluoro-2-(naphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A14"
N-Cyclopropyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A15"
2-[1-(1H-Imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A15.1"
2-(1H-Imidazol-4-ylmethyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A18"
8-Bromo-6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-
1-yl]-9H-purine "A19" ##STR00221## "A20" ##STR00222## "A23"
4-[(R)-2-(Naphthalen-1-yloxymethyl)pyrrolidin-
1-yl]pyrido[2,3-d]pyrimidine "A25"
6-[(R)-2-(Naphthalen-1-yloxymethyl)pyrrolidin-
1-yl]purin-9-yl-amine "A26" 6-[(2R,4R)-4-Fluoro-2-(naphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A28"
6-[(2R,4S)-4-Fluoro-2-(naphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A30"
(3R,5R)-5-(Naphthalen-1-yloxymethyl)-1-
(9H-purin-6-yl)-pyrrolidin-3-ol "A31"
6-(R)-2,2-Difluoro-5-(naphthalen-1-yloxymethyl)pyrrolidin-
1-yl]-9H-purine "A33"
N-[6-(3-{2-[1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-5-
trifluoromethylphenyl}ureidomethyl)-
1H-benzimidazol-2-yl]-acetamide "A34"
N-Methyl-4-[4-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-5-trifluoromethyl-
phenyl}ureidomethyl)phenoxy]pyridine-2-carboxamide "A35"
N-Methyl-4-[4-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-5-trifluoro-
methylphenyl}ureido)phenoxy]pyridine-2-carboxamide "A36"
N-Methyl-4-[3-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-5-trifluoromethyl-
phenyl}ureido)phenoxy]pyridine-2-carboxamide "A37"
6-[(R)-2-(Dibenzofuran-3-yloxymethyl)pyrrolidin-1- yl]-9H-purine
"A38" 4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-9H-carbazole
"A39" Ethyl
1-butyl-2-methyl-5-[(R)-1-(2H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1H-indole-3-carboxylate "A40"
6-[(R)-2-(1H-Indol-4-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A41"
1-{7-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-
ylmethoxy]benzofuran-2-yl}ethanone "A42"
5-Piperidin-1-ylmethyl-8-[(R)-1-(9H-purin-6-yl)pyrroidin-2-yl-
methoxy]quinoline "A43"
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]quinoline "A44"
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]isoquinoline "A45"
7-Benzyloxy-6-methoxy-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinazoline "A46"
4-(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]quinazoline "A47"
2-{2-[2-({4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}amino)ethoxy]ethoxy}ethyl- amine
"A48" N-Methyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A49"
2-Methyl-8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2- yl-methoxy]quinoline
"A50" N-Ethyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A51"
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-
ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A52"
2-Hydroxymethylene-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-2H-naphthalen-1-one "A53"
[1-Oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-
dihydro-1H-naphthalen-(2Z)-ylidene]acetic acid "A54" ##STR00223##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-
1H-naphthalen-2-one "A55" ##STR00224##
6-[(R)-2-(5,6,7,8-Tetrahydronaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine "A56" ##STR00225##
4-Morpholin-4-ylmethyl-8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline "A57" ##STR00226##
1-Chloro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline "A58"
6-{(R)-2-[5-(2-Methoxyethoxy)naphthalen-1-yloxymethyl]-
pyrrolidin-1-yl}-9H-purine "A59"
2-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethyl]-
2H-isoquinolin-1-one "A60"
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl]amine "A61" ##STR00227##
6-[(R)-2-(2-Piperidin-1-ylmethylnaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine "A62" ##STR00228##
6-[(R)-2-(Biphenyl-2-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A63"
6-[(R)-2-(Biphenyl-3-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A64"
6-[(R)-2-(Biphenyl-4-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A65"
Methyl 3-{5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]pyrimidin-2-yl}benzoate "A66"
N-(2-Morpholin-4-ylethyl)-3-{5-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]pyrimidin-2-yl}benzamide "A67"
N-Methyl-2-[1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-naphthalen-(2Z)-ylidene]acetamide "A68"
N-(2-Hydroxypropyl)-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A69" ##STR00229##
N-Cyclopentyl-4-[(R)-1-(9H-purin-6-yl)pyrroidin-2-yl-
methoxy]quinoline-2-carboxamide "A70" ##STR00230##
N-Butyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A71" ##STR00231##
N-Propyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A72" ##STR00232##
6-[(R)-2-(2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine "A73" ##STR00233##
6-[(R)-2-(Benzoxazol-4-yloxymethyl)pyrrolidin-1-yl]-9H-purine "A75"
##STR00234##
2,2,2-Trifluoro-1-{2-methyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]indol-1-yl{ethanone "A77" ##STR00235##
6-{(R)-2-[2-(4-Fluorophenyl)pyrimidin-5-yloxymethyl]-
pyrrolidin-1-yl}-9H-purine "A80" ##STR00236##
N-Cyclobutyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A81" ##STR00237##
N-Pentyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A82" ##STR00238##
2-[1-(4-Chloro-2-methyl-2H-pyrazol-3-yl)meth-(Z)-ylidene]-5-
[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A83" ##STR00239##
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-2-[1-(1H-
pyrazol-3-yl)meth-(Z)-ylidene]-3,4-dihydro-2H-naphthalen-1-one
"A84" ##STR00240##
N-(2-Hydroxyethyl)-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A85" ##STR00241##
N-(3-Hydroxypropyl)-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide "A86" ##STR00242##
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]quinoline "A87"
##STR00243##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]isoquinoline "A88"
##STR00244##
N-(3-Hydroxycyclobutylmethyl)-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide "A89" ##STR00245##
3-Methyl-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline "A92"
N-(2-Morpholin-4-ylethyl)-N-{4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-1-ylmethyl}acetamide "A93"
##STR00246##
4-[(R)-1-(9H-Purin-6-yl)pyrroidin-2-ylmethoxy]quinoline "A94"
##STR00247## N-(2-Morpholin-4-ylethyl)-N-{4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-1-ylmethyl}formamide "A95"
##STR00248##
(3-Morpholin-4-ylpropyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]naphthalen-1-ylmethyl}amine "A96" ##STR00249##
(R)-2-(1H-Imidazol-4-ylmethyl)-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A97"
##STR00250##
(S)-2-(1H-Imidazol-4-ylmethyl)-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A98"
##STR00251##
N-(2-Piperidin-1-ylethyl)-N-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]naphthalen-1-ylmethyl}acetamide "A99" ##STR00252##
N-(1-Methyl-1H-pyrazol-3-ylmethyl)-N-{4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]naplathalen-1-ylmethyl}acetamide "A100"
##STR00253##
N-(2,3-Dihydroxypropyl)-N-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]naphthalen-1-ylmethyl}acetamide "A101" ##STR00254##
N-(2-Piperidin-1-ylethyl)-N-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]naphthalen-1-ylmethyl}formamide "A102" ##STR00255##
N-(1-Methyl-1H-pyrazol-3-ylmethyl)-N-{4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]naphthalen-1-ylmethyl}formamide "A103"
##STR00256##
6-[(R)-2-(2-Benzothiazol-2-ylphenoxymethyl)pyrrolidin-1-yl]-
9H-purine "A104" ##STR00257## 6-[(R)-2-(Imidazo[1,2-a]pyridin-8-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A105" ##STR00258##
6-Chloro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-2-
trifluoromethylquinoline "A106" ##STR00259##
6-{(R)-2-[7-(4-Benzylpiperazin-1-yl)naphthalen-1-yloxymethyl]-
pyrrolidin-1-yl}-9H-purine "A107" ##STR00260##
6-Dimethylamino-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalene-2-sulfonic acid "A108" ##STR00261##
Naphthalen-1-yl[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethyl]-amine
"A109" ##STR00262##
1-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]isoquinoline "A110"
##STR00263##
6-{(R)-2-[4-(4-Propylpiperazin-1-ylmethyl)naphthalen-1-yl-
oxymethyl]pyrrolidin-1-yl}-9H-purine "A111" ##STR00264##
1-(4-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}piperazin-1-yl)ethanone "A112"
##STR00265##
6-{(R)-2-[4-(4-Cyclopentylpiperazin-1-ylmethyl)naphthalen-1-
yloxymethyl]pyrrolidin-1-yl}-9H-purine "A113" ##STR00266##
6-((R)-2-{4-[4-(2-Methoxyethyl)piperazin-1-ylmethyl]-
naphthalen-1-yloxymethyl}pyrrolidin-1-yl)-9H-purine "A114"
##STR00267## ((R)-1-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}pyrrolidin-2-yl)methanol "A115"
##STR00268## 6-[(R)-2-(7-Piperazin-1-ylnaphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A116" ##STR00269##
1-(4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazin-1-yl)ethanone "A117" ##STR00270##
6-Methyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-2-
trifluoromethylquinoline "A118" ##STR00271##
6-[(R)-2-(7-Methoxynaphthalen-1-
yloxymethyl)pyrrolidin-1-yl]-9H-purine "A119" ##STR00272##
6-[(R)-2-(7-Butoxy-5,6-dihydronaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine "A120" ##STR00273## Benzyl
8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-
dihydro-1H-isoquinoline-2-carboxylate "A121" ##STR00274##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-
1H-naphthalen-2-one "A122" ##STR00275##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-
tetrahydroisoquinoline "A123" ##STR00276##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-6-
trifluoromethylquinoline "A124" ##STR00277##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalen-2-ol
"A125" ##STR00278##
(S)-2-(4-Chloro-2-methyl-2H-pyrazol-3-ylmethyl)-5-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]-
3,4-dihydro-2H-naplathalen-1-one "A126" ##STR00279##
(R)-2-(4-Chloro-2-methyl-2H-pyrazol-3-ylmethyl)-5-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]- 3,4-dihydro-2H-naphthalen-1-one
"A127" ##STR00280##
N,N-Diethyl-3-hydroxy-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalene-2-carboxamide "A128" ##STR00281##
3-(4-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}piperazin-1-yl)propionitrile "A129"
##STR00282##
(R)-5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-2-(1H-
pyrazol-3-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one "A130"
##STR00283##
(S)-5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-2-(1H-
pyrazol-3-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one "A131"
##STR00284## 8-{[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-
ylmethyl]-amino}naphthalen-2-ol "A132" ##STR00285##
8-{[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethyl]-
amino}naphthalene-2-sulfonic acid "A133" ##STR00286## tert-Butyl
(6-oxo-6-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}hexyl)carbamate "A134"
##STR00287##
3-(2-{6-[(R)-2-(7-Hydroxynaphthalen-1-yloxymethyl)pyrrolidin-
1-yl]purin-9-yl}ethyl)dihydrofuran-2-one "A135" ##STR00288##
3-{6-[(R)-2-(7-Hydroxynaphthalen-1-yloxymethyl)pyrrolidin-1-
yl]purin-9-yl}propionamide "A136" ##STR00289## Ethyl
5-{6-[(R)-2-(7-hydroxynaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]purin-9-yl}pentanoate "A137" ##STR00290##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-6-
trifluoromethoxyquinoline "A138" ##STR00291##
6-Amino-1-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
3,4-dihydro-1H-isoquinolin-2-yl}hexan-1-one "A139" ##STR00292##
Butyl 6-fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxylate "A140" ##STR00293##
6-Fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy-2-
trifluoromethylquinoline 1-oxide "A141" ##STR00294##
6-Fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxylic acid "A142" ##STR00295##
6-[(R)-2-(7-Nitronaphthalen-1-yloxymethyl)pyrrolidin-
1-yl]-9H-purine "A143" ##STR00296##
(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethyl 2-methylamino-benzoate
"A144" ##STR00297## 8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-
ylmethoxy]naphthalen-2-yl-amine "A145" ##STR00298##
6-{(R)-2-[7-(4-Methylpiperazin-1-yl)naphthalen-1-yloxymethyl]-
pyrrolidin-1-yl}-9H-purine "A146" ##STR00299##
6-[(R)-2-(7-Morpholin-4-ylnaphthalen-1-yloxymethyl)pyrrolidin-
1-yl]-9H-purine "A147" ##STR00300##
4-[(R)-1-(8-Fluoro-9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ol "A148" ##STR00301##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]isoquinoline "A149"
##STR00302##
N-(2-Morpholin-4-ylethyl)-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]quinoline-2-carboxamide "A150" ##STR00303##
N-(3-Morpholin-4-ylpropyl)-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]quinoline-2-carboxamide "A151" ##STR00304## Methyl
5-fluoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-1H-indole-2-carboxylate "A152" ##STR00305##
N,N-Dimethyl-3-[2-(4-methoxyphenyl)ethoxy]-8-[2-(4-methoxy-
phenyl)ethyl]-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalene-2-carboxamide "A153" ##STR00306##
6-{(R)-2-[1-(2,4-Dichlorophenyl)-1H-pyrazol-3-yloxymethyl]-
pyrrolidin-1-yl}-9H-purine "A154" ##STR00307##
1-Ethyl-3-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}urea "A155" ##STR00308##
N-Ethyl-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazine-1-carboxamide "A156"
##STR00309##
N-(Furan-2-ylmethyl)-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]naphthalen-2-yl}piperazine-1-carboxamide "A157"
##STR00310## Ethyl [(4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazine-1-carbonyl)amino]acetate "A158"
##STR00311##
[(4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-methoxy]naphthalen-
2-yl}piperazine-1-carbonyl)amino]acetic acid "A159" ##STR00312##
1-Furan-2-ylmethyl-3-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}urea "A160" ##STR00313## Methyl
(S)-4-benzyloxycarbonylamino-4-{8-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]naphthalen-2-ylcarbamoyl}butyrate "A161"
##STR00314## tert-Butyl
((S)-3-carbamoyl-1-{8-[(R)-1-(9H-purin-6-yl)-pyrrolidin-
2-ylmethoxy]naphthalen-2-ylcarbamoyl}propyl)-carbamate "A162"
##STR00315## tert-Butyl
((R)-2-carbamoyl-1-{8-[(R)-1-(9H-purin-6-yl)-pyrrolidin-
2-ylmethoxy]naphthalen-2-ylcarbamoyl}ethyl)-carbamate "A163"
##STR00316## tert-Butyl ((S)-2-(1H-imidazol-4-
yl)-1-(8-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]naphthalen-2-ylcarbamoyl}ethyl)-carbamate "A164"
##STR00317##
(S)-2-Amino-3-(1H-imidazol-4-yl)-N-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl}propionamide "A165"
##STR00318## N-(1-({8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl})-(S)-2-aminopentan-5-amide "A166"
##STR00319##
4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalen-
2-yl}piperazine-1-carbaldehyde "A167" ##STR00320## tert-Butyl
[2-oxo-2-(4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazin-1-yl)ethyl]carbamate "A168"
##STR00321## 2-Amino-1-(4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazin-1-yl)ethanone "A169" ##STR00322##
1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-
tetrahydronaphthalen-2-yl}pyrrolidin-3-ol "A170" ##STR00323##
1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-
tetrahydronaphthalen-2-yl}azetidin-3-ol "A171" ##STR00324##
N-(1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-
tetrahydronaphthalen-2-yl}pyrrolidin-3-yl)acetamide "A172"
##STR00325##
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]isoquinolin-1-yl}amine "A173" ##STR00326##
N,N-Dimethyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A174"
##STR00327##
N,N-Dimethyl-2-{(S)-1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A175"
##STR00328##
N,N-Dimethyl-2-{(R)-1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A176"
##STR00329##
N-Ethyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A177"
##STR00330##
(R)-2-Amino-N1-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}succinamide "A178" ##STR00331##
(3-Morpholin-4-ylpropyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]isoquinolin-1-yl}amine "A179" ##STR00332##
N-Methyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A180"
##STR00333##
N-(2-Hydroxyethyl)-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)-pyrrolidin-
2-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}acetamide "A181"
##STR00334##
N,N-Dimethyl-N'-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinolin-1-yl}ethane-1,2-diamine "A182" ##STR00335##
N,N-Dimethyl-N'-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinolin-1-yl}propane-1,3-diamine "A183" ##STR00336##
(S)-4-Carboxyamino-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-ylcarbamoyl}butyric acid "A184" ##STR00337##
Ethyl 5-fluoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1H-indole-2-carboxylate "A185" ##STR00338## Ethyl
1-ethoxycarbonylmethyl-5-fluoro-3-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylate "A186"
##STR00339## 3-(2-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yloxy}ethyl)dihydrofuran-2-one "A187"
##STR00340## tert-Butyl
((S)-3-carbamoyl-1-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-isoquinoline-2-
carbonyl}propyl)carbamate "A188" ##STR00341## tert-Butyl
((R)-1-carbamoylmethyl-2-oxo-2-{8-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-isoquinolin-2-
yl}ethyl)carbamate "A189" ##STR00342## tert-Butyl
((S)-1-(1H-imidazol-4-ylmethyl)-2-oxo-2-{8-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-
isoquinolin-2-yl}ethyl)carbamate "A190" ##STR00343##
5-Fluoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1H-indole-2-carboxylic acid "A191" ##STR00344##
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]quinolin-2-ylmethyl}amine "A192" ##STR00345##
(S)-5-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-
dihydro-1H-isoquinoline-2-carbonyl}pyrrolidin-2-one "A193"
##STR00346## tert-Butyl
((S)-5-benzyloxycarbonylamino-6-oxo-6-{8-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-
isoquinolin-2-yl}hexyl)carbamate "A194" ##STR00347##
(R)-3-Amino-4-oxo-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}butyramide "A195"
##STR00348##
(S)-2-Amino-3-(1H-imidazol-4-yl)-1-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-isoquinolin-2-
yl}propan-1-one "A196" ##STR00349##
5-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalen-
2-yloxy}pentanoic acid "A197" ##STR00350##
N-(4-Fluorobenzyl)-5-fluoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxamide "A198" ##STR00351##
2-(4-Fluorophenyl)ethyl 5-fluoro-1-methyl-3-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylate "A199"
##STR00352## Benzyl
((S)-5-amino-1-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinoline-2-carbonyl}pentyl)-carbamate
"A200" ##STR00353##
N-[2-(4-Fluorophenyl)ethyl]-5-fluoro-1-{[2-(4-fluorophenyl]-
ethylcarbamoyl]methyl}-3-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-1H-indole-2-carboxamide "A201" ##STR00354##
(S)-3-Amino-4-oxo-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}butyramide "A202"
##STR00355##
4-Oxo-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-
dihydro-1H-isoquinolin-2-yl}butyramide "A203" ##STR00356##
[2-(4-Fluorophenyl)ethyl]-(2-{5-fluoro-3-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]indol-1-yl}ethyl)amine
or a pharmaceutically usable salt, tautomer or stereoisomer
thereof, or a mixture thereof.
2. A pharmaceutical compostion comprising at least one compound of
the formula I according to claim 1 and/or pharmaceutically usable
salt, tautomer stereoisomer thereof, and a pharmaceutically
acceptable carrier.
Description
SUMMARY Of INVENTION
The invention relates to compounds of the formula I
##STR00002## in which
##STR00003## Z denotes R.sup.1, R.sup.2 each, independently of one
another, denote H, A, Hal, NH.sub.2, (CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mCOOR.sup.6 or (CH.sub.2).sub.mCONH.sub.2, X.sup.1
denotes CH or N, X.sup.2 denotes CH or N, R.sup.3, R.sup.4 each,
independently of one another, denote H, Hal, OH or NH.sub.2,
R.sup.6 denotes H or alkyl having 1-6 C atoms, X denotes O, NH, NA,
OC(.dbd.O) or is absent, Y denotes CH.dbd.CH or (CH.sub.2).sub.n, R
denotes Ar, Het or Carb.sup.1, Ar denotes phenyl, naphthyl or
biphenyl, each of which is unsubstituted or mono-, di-, tri-,
tetra- or pentasubstituted by Hal, A, OR.sup.6, N(R.sup.6).sub.2,
NO.sub.2, CN, COOR.sup.6, CON(R.sup.6).sub.2, NR.sup.6COA,
NR.sup.6SO.sub.2A, COR.sup.6, SO.sub.2N(R.sup.6).sub.2,
S(O).sub.qA, SO.sub.2OH, CH.dbd.CH--CONH(CH.sub.2).sub.pOH,
NHCONH-Het, NHCONHA, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1, O(CH.sub.2).sub.mHet.sup.2,
O(CH.sub.2).sub.mCOOR.sup.6,
##STR00004## (CH.sub.2).sub.mHet,
CH.sub.2NH[(CH.sub.2).sub.2O].sub.q[(CH.sub.2).sub.2O].sub.q(CH.sub.2).su-
b.pNH.sub.2, CH.sub.2N(COA)CH.sub.2CH(OH)CH.sub.2OH,
CH.sub.2NH(CH.sub.2).sub.qHet, CH.sub.2N(COA)(CH.sub.2).sub.qHet,
CH.sub.2N(CHO)(CH.sub.2).sub.qHet, COHet,
NHCOCH[(CH.sub.2).sub.mCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mCOOH]NHCOOH,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2, CH.dbd.CH--COOR.sup.6
and/or CH.dbd.CH--CON(R.sup.6).sub.2, Het denotes a mono-, bi- or
tricyclic saturated, unsaturated or aromatic heterocycle having 1
to 4 N, and/or O and/or S atoms which is unsubstituted or mono-,
di- or trisubstituted by Hal, A, (CH.sub.2).sub.mOR.sup.6,
N(R.sup.6).sub.2, NO.sub.2, (CH.sub.2).sub.mCN,
(CH.sub.2).sub.mCOOR.sup.6, CONH(CH.sub.2).sub.mCOOH,
CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen), and in
which one N may also be oxidised, Cyc denotes cycloalkylene having
3-7 C atoms, Ar.sup.1 denotes phenyl which is unsubstituted or
mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, OR.sup.6,
COOR.sup.6, CON(R.sup.6).sub.2, NR.sup.6COA and/or
CONH(CH.sub.2).sub.pHet.sup.2, Carb.sup.1 denotes
##STR00005## R.sup.5 denotes OR.sup.6, COOR.sup.6,
CON(R.sup.6).sub.2 or Het.sup.1, R.sup.7 denotes
(CH.sub.2).sub.rCON(R.sup.6).sub.2,
(CH.sub.2).sub.rCON[(CH.sub.2CH.sub.2)OH].sub.2 or
(CH.sub.2).sub.rCONH(CH.sub.2CH.sub.2)OH, Het.sup.1 denotes
imidazolyl, pyrazolyl or 4-chloro-2-methylpyrazolyl, Het.sup.2
denotes a monocyclic aromatic or saturated heterocycle having 1 to
2 N, and/or O and/or S atoms which is unsubstituted or mono-, di-
or trisubstituted by Hal, A, OR.sup.6, NHCOA, N(R.sup.6).sub.2
and/or .dbd.O (carbonyl oxygen), A denotes unbranched or branched
alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by
F, Cl, Br and/or OH, or cyclic alkyl having 3-7 C atoms, Hal
denotes F, Cl, Br or I, m denotes 0, 1, 2, 3, 4, 5 or 6, n denotes
1 or 2, p denotes 1, 2, 3 or 4, q denotes 0, 1, 2, 3 or 4, r
denotes 0, 1 or 2, and pharmaceutically usable salts, tautomers and
stereoisomers thereof, including mixtures thereof in all
ratios.
The invention was based on the object of finding novel compounds
having valuable properties, in particular those which can be used
for the preparation of medicaments.
It has been found that the compounds of the formula I and salts
thereof have very valuable pharmacological properties while being
well tolerated.
In particular, they exhibit a regulatory, modulatory and/or
inhibiting action on metal proteases, preferably on methionine
aminopeptidase (MetAP), particularly on the sub-type MetAP-2.
They can be used as medicaments against cancer, but also as
medicaments which positively influence fat metabolism, but also as
medicaments against inflammation.
Other purine derivatives for combating cancer are disclosed in WO
2007/017069.
WO 01/79157 describes substituted hydrazides and N-alkoxyamides
which have MetAP-2 inhibitory activity and can be used for the
inhibition of angiogenesis, in particular for the treatment of
diseases, such as, for example, cancer, whose development is
dependent on angiogenesis.
WO 02/081415 describes MetAP-2 inhibitors which can be used for the
treatment of cancer, haemangioma, proliferative retinopathy,
rheumatoid arthritis, atherosclerotic neovascularisation,
psoriasis, ocular neovascularisation and obesity.
WO 2008/011114 describes compounds as angiogenesis inhibitors and
MetAP-2 inhibitors which can be used for the treatment of lymphoid
leukaemia and lymphoma.
The action of the compounds according to the invention against
cancer lies in particular in their action against angiogenesis.
Angiogenesis inhibition has proven helpful in more than 70
diseases, such as, for example, ovarian cancer (F. Spinella et al.
J. Cardiovasc. Pharmacol. 2004, 44, S140), breast cancer (A.
Morabito et al. Crit. Rev. Oncol./Hematol. 2004, 49, 91), prostate
cancer (B. Nicholson et al. Cancer Metastas. Rev. 2001, 20, 297),
diabetic blindness, psoriasis and macular degeneration (E. Ng et
al. Can. J. Ophthalmol. 2005, 23, 3706).
Proteases regulate many different cell processes, particularly the
modulation of peptides and proteins, particularly protein
conversion, protein ripening and signal peptide processing, the
breakdown of abnormal proteins and the deactivation/activation of
regulatory proteins. In particular, the amino-terminal modification
of nascent polypeptides represents the most frequent modulation.
Aminoproteases are metalloproteases which cleave off amino acids
from the unprotected N terminus of peptides or proteins, which can
be carried out in either a co- or post-translatory manner.
Methionine aminopeptidase (MetAP) cleaves terminal methionine of
nascent peptides in particular if the penultimate amino acid is
small and uncharged (for example Gly, Ala, Ser, Thr, Val, Pro or
Cys).
In many disease processes, angiogenesis is either causally at the
centre of the disease or has a worsening effect on the progression
of the disease. In cancer events, for example, angiogenesis results
in the tumour increasing in size and being able to enter other
organs. Other diseases in which angiogenesis plays an important
role are psoriasis, arthrosis, arteriosclerosis and eye diseases,
such as diabetic retinopathy, age-induced macular degeneration,
rubeosis iridis or neovascular glaucoma, furthermore in
inflammations. The compounds of the formula I on which this
invention is based, compositions which comprise these compounds,
and the processes described can thus be employed for the treatment
of these diseases.
Accordingly, the compounds according to the invention or a
pharmaceutically acceptable salt thereof are administered for the
treatment of cancer, including solid carcinomas, such as, for
example, carcinomas (of the lungs, pancreas, thyroid, bladder or
colon), myeloid diseases (for example myeloid leukaemia) or
adenomas (for example villous colon adenoma).
The tumours furthermore include monocytic leukaemia, brain,
urogenital, lymphatic system, stomach, laryngeal and lung
carcinoma, including lung adenocarcinoma and small-cell lung
carcinoma, pancreatic and/or breast carcinoma.
The present invention therefore relates to compounds according to
the invention as medicaments and/or medicament active ingredients
in the treatment and/or prophylaxis of the said diseases and to the
use of compounds according to the invention for the preparation of
a pharmaceutical for the treatment and/or prophylaxis of the said
diseases and to a process for the treatment of the said diseases
comprising the administration of one or more compounds according to
the invention to a patient in need of such an administration.
It can be shown that the compounds according to the invention have
an anti-carcinogenic action. The compounds according to the
invention are administered to a patient having a disease, for
example to inhibit tumour growth, to reduce inflammation associated
with a lymphoproliferative disease, to inhibit transplant rejection
or neurological damage due to tissue repair, etc. The present
compounds are suitable for prophylactic or therapeutic purposes. As
used herein, the term "treatment" is used to refer to both the
prevention of diseases and the treatment of pre-existing
conditions. The prevention of proliferation/vitality is achieved by
administration of the compounds according to the invention prior to
the development of overt disease, for example for preventing tumour
growth. Alternatively, the compounds are used for the treatment of
ongoing diseases by stabilising or improving the clinical symptoms
of the patient.
The host or patient can belong to any mammalian species, for
example a primate species, particularly humans; rodents, including
mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc.
Animal models are of interest for experimental investigations,
providing a model for treatment of a human disease.
The susceptibility of a particular cell to treatment with the
compounds according to the invention can be determined by in vitro
testing. Typically, a culture of the cell is incubated with a
compound according to the invention at various concentrations for a
period of time which is sufficient to allow the active agents to
induce cell death or to inhibit cell proliferation, cell vitality
or migration, usually between about one hour and one week. In vitro
testing can be carried out using cultivated cells from a biopsy
sample. The amount of cells remaining after the treatment are then
determined.
The dose varies depending on the specific compound used, the
specific disease, the patient status, etc. A therapeutic dose is
typically sufficient considerably to reduce the undesired cell
population in the target tissue, while the viability of the patient
is maintained. The treatment is generally continued until a
considerable reduction has occurred, for example an at least about
50% reduction in the cell burden, and may be continued until
essentially no more undesired cells are detected in the body.
It has been found that the compounds according to the invention
cause specific inhibition of MetAP-2. The compounds according to
the invention preferably exhibit an advantageous biological
activity which can be detected in the tests described, for example,
herein. In such tests, the compounds according to the invention
exhibit and cause an inhibiting effect, which is usually documented
by IC.sub.50 values in a suitable range, preferably in the
micromolar range and more preferably in the nanomolar range.
In addition, the compounds according to the invention can be used
to achieve additive or synergistic effects in certain existing
cancer chemotherapies and radiotherapies and/or to restore the
efficacy of certain existing cancer chemotherapies and
radiotherapies.
Compounds of the formula I are also taken to mean the hydrates and
solvates of these compounds, furthermore pharmaceutically usable
derivatives.
The invention also relates to the optically active forms
(stereoisomers), salts, the enantiomers, the racemates, the
diastereomers and the hydrates and solvates of these compounds. The
term solvates of the compounds is taken to mean adductions of inert
solvent molecules onto the compounds which form owing to their
mutual attractive force. Solvate are, for example, mono- or
dihydrates or alkoxides.
The term pharmaceutically usable derivatives is taken to mean, for
example, the salts of the compounds according to the invention and
also so-called pro-drug compounds.
The term prodrug derivatives is taken to mean compounds of the
formula I which have been modified by means of, for example, alkyl
or acyl groups, sugars or oligopeptides and which are rapidly
cleaved in the organism to form the effective compounds according
to the invention.
These also include biodegradable polymer derivatives of the
compounds according to the invention, as described, for example, in
Int. J. Pharm. 115, 61-67 (1995).
The expression "effective amount" denotes the amount of a
medicament or of a pharmaceutical active ingredient which causes in
a tissue, system, animal or human a biological or medical response
which is sought or desired, for example, by a researcher or
physician.
In addition, the expression "therapeutically effective amount"
denotes an amount which, compared with a corresponding subject who
has not received this amount, has the following consequence:
improved treatment, healing, prevention or elimination of a
disease, syndrome, condition, complaint, disorder or side effects
or also the reduction in the advance of a disease, condition or
disorder.
The expression "therapeutically effective amount" also encompasses
the amounts which are effective for increasing normal physiological
function.
The invention also relates to the use of mixtures of the compounds
of the formula I, for example mixtures of two diastereomers, for
example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or
1:1000.
These are particularly preferably mixtures of stereoisomeric
compounds.
The invention relates to the compounds of the formula I and salts
thereof and to a process for the preparation of compounds of the
formula I and pharmaceutically usable salts, tautomers and
stereoisomers thereof, characterised in that
a compound of the formula II
##STR00006## in which R.sup.3, R.sup.4, X, Y and R have the
meanings indicated in claim 1, is reacted with a compound of the
formula III Z--Cl III in which Z has the meaning indicated in claim
1, and/or a base or acid of the formula I is converted into one of
its salts.
Above and below, the radicals R, X, Y, Z, R.sup.3 and R.sup.4 have
the meanings indicated for the formula I, unless expressly
indicated otherwise.
A denotes alkyl, is unbranched (linear) or branched, and has 1, 2,
3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,
furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,
1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or
4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl,
1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,
1,1,2- or 1,2,2-trimethylpropyl, further preferably, for example,
trifluoromethyl.
A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5
or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,
pentafluoroethyl or 1,1,1-trifluoroethyl.
Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl. R.sup.1 denotes H, A, Hal, NH.sub.2,
(CH.sub.2).sub.mHet.sup.2, (CH.sub.2).sub.mCOOR.sup.6 or
(CH.sub.2).sub.mCONH.sub.2. R.sup.2 preferably denotes H.
Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- or
p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or
p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or
p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or
p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-hydroxyphenyl,
o-, m- or p-methoxyphenyl, o-, m- or p-methylsulfonylphenyl, o-, m-
or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or
p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or
p-aminosulfonylphenyl, o-, m- or p-methylamino-sulfonylphenyl, o-,
m- or p-aminocarbonylphenyl, o-, m- or p-carboxyphenyl, o-, m- or
p-methoxycarbonylphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m-
or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or
p-cyanophenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or
3,4,5-trichlorophenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl,
2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl or
2,5-dimethyl-4-chlorophenyl; furthermore naphthyl or biphenyl.
Ar furthermore preferably denotes phenyl, naphthyl or biphenyl,
each of which is unsubstituted or mono-, di-, tri-, tetra- or
pentasubstituted by Hal, A, OR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
CN, COOR.sup.6, CON(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2N(R.sup.6).sub.2, S(O).sub.qA, SO.sub.2OH,
CH.dbd.CH--CONH(CH.sub.2).sub.pOH, NHCONH-Het, NHCONHA,
(CH.sub.2).sub.mAr.sup.1, O(CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mHet.sup.2, O(CH.sub.2).sub.mCOOR.sup.6,
##STR00007## (CH.sub.2).sub.mHet,
CH.sub.2NH[(CH.sub.2).sub.2O].sub.q[(CH.sub.2).sub.2O].sub.q(CH.sub.2).su-
b.pNH.sub.2, CH.sub.2N(COA)CH.sub.2CH(OH)CH.sub.2OH,
CH.sub.2NH(CH.sub.2).sub.qHet, CH.sub.2N(COA)(CH.sub.2).sub.qHet,
CH.sub.2N(CHO)(CH.sub.2).sub.qHet, COHet,
NHCOCH[(CH.sub.2).sub.mCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mCOOH]NHCOOH,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2, CH.dbd.CH--COOR.sup.6
and/or CH.dbd.CH--CON(R.sup.6).sub.2.
Irrespective of further substitutions, Het denotes, for example, 2-
or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or
5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-,
4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or
5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,
furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,
1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl,
1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,
1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,
1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-,
2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or
5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-,
4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or
7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6-
or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl,
1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or
8-cinnolinyl, 2-; 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or
6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,
further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,
2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.
The heterocyclic radicals may also be partially or fully
hydrogenated. Unsubstituted Het can thus also denote, for example,
2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or
5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,
tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or
-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2-
or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,
2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3-
or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,
1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3-
or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or
-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl,
hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or
-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-,
-2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,
-2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7-
or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably
2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,
2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,
3,4-(difluoro-methylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or
6-yl, 2,3-(2-oxomethylene-dioxy)phenyl or also
3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore
preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het furthermore preferably denotes a mono-, bi- or tricyclic
saturated, unsaturated or aromatic heterocycle having 1 to 4 N,
and/or O and/or S atoms which is unsubstituted or mono-, di- or
trisubstituted by Hal, A, OR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
(CH.sub.2).sub.mCN, (CH.sub.2).sub.mCOOR.sup.6,
CONH(CH.sub.2).sub.mCOOH, CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen)
and in which one N may also be oxidised,
Het particularly preferably denotes pyridazinyl, pyrazolyl,
benzimidazolyl, pyridyl, dibenzofuranyl, carbazolyl, indolyl,
dihydroindolyl, benzofuranyl, dihydrobenzofuranyl, piperazinyl,
morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl,
dihydroisoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
purinyl, naphthyridinyl, pyrimidinyl, indazolyl, furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
thiadiazole, benzothiazolyl, imidazo[1,2-a]pyridinyl,
1,3-benzodioxolyl or benzoxazolyl, each of which is unsubstituted
or mono-, di- or trisubstituted by Hal, A,
(CH.sub.2).sub.mOR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
(CH.sub.2).sub.mCN, (CH.sub.2).sub.mCOOR.sup.6,
CONH(CH.sub.2).sub.mCOOH, CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen),
and in which one N may also be oxidised,
Cyc preferably denotes cyclobutylene, cyclopentylene or
cyclohexylene. Z preferably denotes
##STR00008## furthermore
##STR00009## Z furthermore preferably denotes
##STR00010##
R denotes Ar, Het or Carb.sup.1, preferably Het or Carb.sup.1.
Het.sup.2 preferably denotes furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl,
piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl,
dihydrofuranyl or tetrahydrofuranyl, each of which is unsubstituted
or mono- or disubstituted by unsubstituted or mono- or
disubstituted by A, OR.sup.6, NHCOA and/or .dbd.O (carbonyl
oxygen).
Hal preferably denotes F, Cl or Br, but also I, particularly
preferably F or Cl.
Throughout the invention, all radicals which occur more than once
may be identical or different, i.e. are independent of one
another.
The compounds of the formula I may have one or more chiral centres
and can therefore occur in various stereoisomeric forms. The
formula I encompasses all these forms.
Accordingly, the invention relates, in particular, to the compounds
of the formula I in which at least one of the said radicals has one
of the preferred meanings indicated above. Some preferred groups of
compounds may be expressed by the following sub-formulae Ia to If,
which conform to the formula I and in which the radicals not
designated in greater detail have the meaning indicated for the
formula I, but in which in Ia Z denotes
##STR00011## in Ib Het denotes pyridazinyl, pyrazolyl,
benzimidazolyl, pyridyl, dibenzofuranyl, carbazolyl, indolyl,
dihydroindolyl, benzofuranyl, dihydrobenzofuranyl, piperazinyl,
morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl,
dihydroisoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
purinyl, naphthyridinyl, pyrimidinyl, indazolyl, furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
thiadiazole, benzothiazolyl, imidazo[1,2-a]pyridinyl,
1,3-benzodioxolyl or benzoxazolyl, each of which is unsubstituted
or mono-, di- or trisubstituted by Hal, A,
(CH.sub.2).sub.mOR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
(CH.sub.2).sub.mCN, (CH.sub.2).sub.mCOOR.sup.6,
CONH(CH.sub.2).sub.mCOOH, CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen), and in
which one N may also be oxidised; in Ic Het.sup.2 denotes furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,
pyridyl, pyrimidinyl, piperazinyl, morpholinyl, piperidinyl,
pyrrolidinyl, azetidinyl, dihydrofuranyl or tetrahydrofuranyl, each
of which is unsubstituted or mono- or disubstituted by A, OR.sup.6,
NHCOA and/or .dbd.O (carbonyl oxygen); in Id Z denotes
##STR00012## R.sup.1, R.sup.2 each, independently of one another,
denote H, A, Hal, NH.sub.2, (CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mCOOR.sup.6 or (CH.sub.2).sub.mCONH.sub.2, R.sup.3,
R.sup.4 each, independently of one another, denote H, Hal, OH or
NH.sub.2, R.sup.6 denotes H or alkyl having 1-6 C atoms, X denotes
O, NH, NA, OC(.dbd.O) or is absent, Y denotes CH.dbd.CH or
(CH.sub.2).sub.n, R denotes Ar, Het or Carb.sup.1, Ar denotes
phenyl, naphthyl or biphenyl, each of which is unsubstituted or
mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, OR.sup.6,
N(R.sup.6).sub.2, NO.sub.2, CN, COOR.sup.6, CON(R.sup.6).sub.2,
NR.sup.6COA, NR.sup.6SO.sub.2A, COR.sup.6,
SO.sub.2N(R.sup.6).sub.2, S(O).sub.qA, SO.sub.2OH,
CH.dbd.CH--CONH(CH.sub.2).sub.pOH, NHCONH-Het, NHCONHA,
(CH.sub.2).sub.mAr.sup.1, O(CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mHet.sup.2, O(CH.sub.2).sub.mCOOR.sup.6,
##STR00013## (CH.sub.2).sub.mHet,
CH.sub.2NH[(CH.sub.2).sub.2O].sub.q[(CH.sub.2).sub.2O].sub.q(CH.sub.2).su-
b.pNH.sub.2, CH.sub.2N(COA)CH.sub.2CH(OH)CH.sub.2OH,
CH.sub.2NH(CH.sub.2).sub.qHet, CH.sub.2N(COA)(CH.sub.2).sub.qHet,
CH.sub.2N(CHO)(CH.sub.2).sub.qHet, COHet,
NHCOCH[(CH.sub.2).sub.mCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mCOOH]NHCOOH,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2, CH.dbd.CH--COOR.sup.6
and/or CH.dbd.CH--CON(R.sup.6).sub.2, Het denotes pyridazinyl,
pyrazolyl, benzimidazolyl, pyridyl, dibenzofuranyl, carbazolyl,
indolyl, dihydroindolyl, benzofuranyl, dihydrobenzofuranyl,
piperazinyl, morpholinyl, quinolinyl, isoquinolinyl,
dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
purinyl, naphthyridinyl, pyrimidinyl, indazolyl, furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
thiadiazole, benzothiazolyl imidazo[1,2-a]pyridinyl,
1,3-benzodioxolyl or benzoxazolyl, each of which is unsubstituted
or mono-, di- or trisubstituted by Hal, A,
(CH.sub.2).sub.mOR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
(CH.sub.2).sub.mCN, (CH.sub.2).sub.mCOOR.sup.6,
CONH(CH.sub.2).sub.mCOOH, CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen), and in
which one N may also be oxidised, Cyc denotes cycloalkylene having
3-7 C atoms, Ar.sup.1 denotes phenyl which is unsubstituted or
mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, OR.sup.6,
COOR.sup.6, CON(R.sup.6).sub.2, NR.sup.6COA and/or
CONH(CH.sub.2).sub.pHet.sup.2, Carb.sup.1 denotes
##STR00014## R.sup.5 denotes OR.sup.6, COOR.sup.6,
CON(R.sup.6).sub.2 or Het.sup.1, R.sup.7 denotes
(CH.sub.2).sub.rCON(R.sup.6).sub.2,
(CH.sub.2).sub.rCON[(CH.sub.2CH.sub.2)OH].sub.2 or
(CH.sub.2).sub.rCONH(CH.sub.2CH.sub.2)OH, Het.sup.1 denotes
imidazolyl, pyrazolyl or 4-chloro-2-methylpyrazolyl, Het.sup.2
denotes furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
imidazolyl, pyridyl, pyrimidinyl, piperazinyl, morpholinyl,
piperidinyl, pyrrolidinyl, azetidinyl, dihydrofuranyl or
tetrahydrofuranyl, each of which is unsubstituted or mono- or
disubstituted by A, OR.sup.6, NHCOA and/or .dbd.O (carbonyl
oxygen), A denotes unbranched or branched alkyl having 1-10 C
atoms, in which 1-7 H atoms may be replaced by F, Cl, Br and/or OH,
or cyclic alkyl having 3-7 C atoms, Hal denotes F, Cl, Br or I, m
denotes 0, 1, 2, 3, 4, 5 or 6, n denotes 1 or 2, p denotes 1, 2, 3
or 4, q denotes 0, 1, 2, 3 or 4, r denotes 0, 1 or 2; in Ie Z
denotes
##STR00015## in If Z denotes
##STR00016## R.sup.1, R.sup.2 each, independently of one another,
denote H, A, Hal, NH.sub.2, (CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mCOOR.sup.6 or (CH.sub.2).sub.mCONH.sub.2, R.sup.3,
R.sup.4 each, independently of one another, denote H, Hal, OH or
NH.sub.2, R.sup.6 denotes H or alkyl having 1-6 C atoms, X denotes
O, NH, NA, OC(.dbd.O) or is absent, Y denotes CH.dbd.CH or
(CH.sub.2).sub.n, R denotes Ar, Het or Carb.sup.1, Ar denotes
phenyl, naphthyl or biphenyl, each of which is unsubstituted or
mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, OR.sup.6,
N(R.sup.6).sub.2, NO.sub.2, CN, COOR.sup.6, CON(R.sup.6).sub.2,
NR.sup.6COA, NR.sup.6SO.sub.2A, COR.sup.6,
SO.sub.2N(R.sup.6).sub.2, S(O).sub.qA, SO.sub.2OH,
CH.dbd.CH--CONH(CH.sub.2).sub.pOH, NHCONH-Het, NHCONHA,
(CH.sub.2).sub.mAr.sup.1, O(CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mHet.sup.2, O(CH.sub.2).sub.mCOOR.sup.6,
##STR00017## (CH.sub.2).sub.mHet,
CH.sub.2NH[(CH.sub.2).sub.2O].sub.q[(CH.sub.2).sub.2O].sub.q(CH.sub.2).su-
b.pNH.sub.2, CH.sub.2N(COA)CH.sub.2CH(OH)CH.sub.2OH,
CH.sub.2NH(CH.sub.2).sub.qHet, CH.sub.2N(COA)(CH.sub.2).sub.qHet,
CH.sub.2N(CHO)(CH.sub.2).sub.qHet, COHet,
NHCOCH[(CH.sub.2).sub.mCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mCOOH]NHCOOH,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
NHCOCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
NHCOCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2, CH.dbd.CH--COOR.sup.6
and/or CH.dbd.CH--CON(R.sup.6).sub.2, Het denotes pyridazinyl,
pyrazolyl, benzimidazolyl, pyridyl, dibenzofuranyl, carbazolyl,
indolyl, dihydroindolyl, benzofuranyl, dihydrobenzofuranyl,
piperazinyl, morpholinyl, quinolinyl, isoquinolinyl,
dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
purinyl, naphthyridinyl, pyrimidinyl, indazolyl, furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
thiadiazole, benzothiazolyl, imidazo[1,2-a]pyridinyl,
1,3-benzodioxolyl or benzoxazolyl, each of Which is unsubstituted
or mono-, di- or trisubstituted by Hal, A,
(CH.sub.2).sub.mOR.sup.6, N(R.sup.6).sub.2, NO.sub.2,
(CH.sub.2).sub.mCN, (CH.sub.2).sub.mCOOR.sup.6,
CONH(CH.sub.2).sub.mCOOH, CONH(CH.sub.2).sub.mHet.sup.2,
CO(CH.sub.2).sub.mNH(CH.sub.2).sub.rCOOA,
COO(CH.sub.2).sub.mAr.sup.1,
(CH.sub.2).sub.rCONH(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mCONH.sub.2]NH.sub.2,
COCH[(CH.sub.2).sub.mCONH.sub.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NHCOOA,
COCH[(CH.sub.2).sub.mHet.sup.2]NH.sub.2,
COCH[(CH.sub.2).sub.mNHCOOA]NHCOO(CH.sub.2).sub.mAr.sup.1,
COCH[(CH.sub.2).sub.mNH.sub.2]NHCOO(CH.sub.2).sub.mAr.sup.1,
CO(CH.sub.2).sub.mN(R.sup.6).sub.2, NR.sup.6COA, NR.sup.6SO.sub.2A,
COR.sup.6, SO.sub.2NR.sup.6, S(O).sub.qA,
NHCONH--(CH.sub.2).sub.m-Cyc-OR.sup.6,
CONH(CH.sub.2).sub.pOR.sup.6, O(CH.sub.2).sub.pOR.sup.6, CHO,
(CH.sub.2).sub.mHet.sup.2, COHet.sup.2,
(CH.sub.2).sub.rNH(CH.sub.2).sub.mHet.sup.2,
(CH.sub.2).sub.mNH(CH.sub.2).sub.mAr.sup.1,
NH(CH.sub.2).sub.pN(R.sup.6).sub.2, (CH.sub.2).sub.mAr.sup.1,
O(CH.sub.2).sub.mAr.sup.1 and/or .dbd.O (carbonyl oxygen), and in
which one N may also be oxidised, Cyc denotes cycloalkylene having
3-7 C atoms, Ar.sup.1 denotes phenyl which is unsubstituted or
mono-, di-, i-, tetra- or pentasubstituted by Hal, A, OR.sup.6,
COOR.sup.6, CON(R.sup.6).sub.2, NR.sup.6COA and/or
CONH(CH.sub.2).sub.pHet.sup.2, Carb.sup.1 denotes
##STR00018## R.sup.5 denotes OR.sup.6, COOR.sup.6,
CON(R.sup.6).sub.2 or Het.sup.1, R.sup.7 denotes
(CH.sub.2).sub.rCON(R.sup.6).sub.2,
(CH.sub.2).sub.rCON[(CH.sub.2CH.sub.2)OH].sub.2 or
(CH.sub.2).sub.rCONH(CH.sub.2CH.sub.2)OH, Het.sup.1 denotes
imidazolyl, pyrazolyl or 4-chloro-2-methylpyrazolyl, Het.sup.2
denotes furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
imidazolyl, pyridyl, pyrimidinyl, piperazinyl, morpholinyl,
piperidinyl, pyrrolidinyl, azetidinyl, dihydrofuranyl or
tetrahydrofuranyl, each of which is unsubstituted or mono- or
disubstituted by A, OR.sup.6, NHCOA and/or .dbd.O (carbonyl
oxygen), A denotes unbranched or branched alkyl having 1-10 C
atoms, in which 1-7 H atoms may be replaced by F, Cl, Br and/or OH,
or cyclic alkyl having 3-7 C atoms, Hal denotes F, Cl, Br or I, m
denotes 0, 1, 2, 3, 4, 5 or 6, n denotes 1 or 2, p denotes 1, 2, 3
or 4, q denotes 0, 1, 2, 3 or 4, r denotes 0, 1 or 2; and
pharmaceutically usable salts, tautomers and stereoisomers thereof,
including mixtures thereof in all ratios.
The compounds of the formula I and also the starting materials for
their preparation are, in addition, prepared by methods known per
se, as described in the literature (for example in the standard
works, such as Houben-Weyl, Methadon der organischen Chemie
[Methods of Organic Chemistry], Georg-Thieme-Ver-lag, Stuttgart),
to be precise under reaction conditions which are known and
suitable for the said reactions. Use can also be made here of
variants known per se which are not mentioned here in greater
detail.
Compounds of the formula I can preferably be obtained by reacting
compounds of the formula II with a compound of the formula III.
The compounds of the formula II and of the formula III are
generally known. If they are novel, however, they can be prepared
by methods known per se.
The reaction is carried out in an inert solvent and is generally
carried out in the presence of an acid-binding agent, preferably an
organic base, such as DIPEA, triethylamine, dimethylaniline,
pyridine or quinoline.
The addition of an alkali or alkaline-earth metal hydroxide,
carbonate or bicarbonate or another salt of a weak acid of the
alkali or alkaline-earth metals, preferably of potassium, sodium,
calcium or caesium, may also be favourable.
Depending on the conditions used, the reaction time is between a
few minutes and 14 days, the reaction temperature is between about
-15.degree. and 150.degree., normally between 40.degree. and
130.degree., particularly preferably between 60.degree. and
110.degree. C.
Suitable inert solvents are, for example, hydrocarbons, such as
hexane, petroleum ether, benzene, toluene or xylene; chlorinated
hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, chloroform or dichloromethane; alcohols, such as
methanol, ethanol, isopropanol, n-propanol, n-butanol or
tert-butanol; ethers, such as diethyl ether, diisopropyl ether,
tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene
glycol monomethyl or monoethyl ether, ethylene glycol dimethyl
ether (diglyme); ketones, such as acetone or butanone; amides, such
as acetamide, dimethylacetamide or dimethylformamide (DMF);
nitriles, such as acetonitrile; sulfoxides, such as dimethyl
sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as
formic acid or acetic acid; nitro compounds, such as nitromethane
or nitrobenzene; esters, such as ethyl acetate, or mixtures of the
said solvents.
Particular preference is given to glycol ethers, such as ethylene
glycol monomethyl ether, THF, dichloromethane and/or DMF.
Pharmaceutical Salts and Other Forms
The said compounds according to the invention can be used in their
final non-salt form. On the other hand, the present invention also
encompasses the use of these compounds in the form of their
pharmaceutically acceptable salts, which can be derived from
various organic and inorganic acids and bases by procedures known
.in the art. Pharmaceutically acceptable salt forms of the
compounds of the formula I are for the most part prepared by
conventional methods. If the compound of the formula I contains a
carboxyl group; one of its suitable salts can be formed by reacting
the compound with a suitable base to give the corresponding
base-addition salt. Such bases are, for example, alkali metal
hydroxides, including potassium hydroxide, sodium hydroxide and
lithium hydroxide; alkaline-earth metal hydroxides, such as barium
hydroxide and calcium hydroxide; alkali metal alkoxides, for
example potassium ethoxide and sodium propoxide; and various
organic bases, such as piperidine, diethanolamine and
N-methylglutamine. The aluminium salts of the compounds of the
formula I are likewise included. In the case of certain compounds
of the formula I, acid-addition salts can be formed by treating
these compounds with pharmaceutically acceptable organic and
inorganic acids, for example hydrogen halides, such as hydrogen
chloride, hydrogen bromide or hydrogen iodide, other mineral acids
and corresponding salts thereof, such as sulfate, nitrate or
phosphate and the like, and alkyl- and monoarylsulfonates, such as
ethanesulfonate, toluenesulfonate and benzenesulfonate, and other
organic acids and corresponding salts thereof, such as acetate,
trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate,
salicylate, ascorbate and the like. Accordingly, pharmaceutically
acceptable acid-addition salts of the compounds of the formula I
include the following: acetate, adipate, alginate, arginate,
aspartate, benzoate, benzenesulfonate (besylate), bisulfate,
bisulfite, bromide, butyrate, camphorate, camphorsulfonate,
caprylate, chloride, chlorobenzoate, citrate,
cyclopentanepropionate, digluconate, dihydrogenphosphate,
dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate,
galacterate (from mucic acid), galacturonate, glucoheptanoate,
gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,
isobutyrate, lactate, lactobionate, malate, maleate, malonate,
mandelate, metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,
3-phenylpropionate, phosphate, phosphonate, phthalate, but this
does not represent a restriction.
Furthermore, the base salts of the compounds according to the
invention include aluminium, ammonium, calcium, copper, iron(III),
iron(II), lithium, magnesium, manganese(III), manganese(II),
potassium, sodium and zinc salts, but this is not intended to
represent a restriction. Of the above-mentioned salts, preference
is given to ammonium; the alkali metal salts sodium and potassium,
and the alkaline-earth metal salts calcium and magnesium. Salts of
the compounds of the formula I which are derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary and tertiary amines, substituted amines, also
including naturally occurring substituted amines, cyclic amities,
and basic ion exchanger resins, for example arginine, betaine,
caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine
(benzathine), dicyclohexylamine, diethanolamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lidocaine,
lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethanolamine, triethylamine, trimethylamine, tripropylamine and
tris(hydroxymethyl)methylamine (tromethamine), but this is not
intended to represent a restriction.
Compounds of the present invention which contain basic
nitrogen-containing groups can be quaternised using agents such as
(C.sub.1-C.sub.4)alkyl halides, for example methyl, ethyl,
isopropyl and tert-butyl chloride, bromide and iodide;
di(C.sub.1-C.sub.4)alkyl sulfates, for example dimethyl, diethyl
and diamyl sulfate; (C.sub.10-C.sub.18)alkyl halides, for example
decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and
iodide; and aryl(C.sub.1-C.sub.4)alkyl halides, for example benzyl
chloride and phenethyl bromide. Both water- and oil-soluble
compounds according to the invention can be prepared using such
salts.
The above-mentioned pharmaceutical salts which are preferred
include acetate, trifluoroacetate, besylate, citrate, fumarate,
gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide,
isethionate, mandelate, meglumine, nitrate, oleate, phosphonate,
pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate,
tartrate, thiomalate, tosylate and tromethamine, but this is not
intended to represent a restriction.
The acid-addition salts of basic compounds of the formula I are
prepared by bringing the free base form into contact with a
sufficient amount of the desired acid, causing the formation of the
salt in a conventional manner. The free base can be regenerated by
bringing the salt form into contact with a base and isolating the
free base in a conventional manner. The free base forms differ in a
certain respect from the corresponding salt forms thereof with
respect to certain physical properties, such as solubility in polar
solvents; for the purposes of the invention, however, the salts
otherwise correspond to the respective free base forms thereof.
As mentioned, the pharmaceutically acceptable base-addition salts
of the compounds of the formula I are formed with metals or amines,
such as alkali metals and alkaline-earth metals or organic amines.
Preferred metals are sodium, potassium, magnesium and calcium.
Preferred organic amines are N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methyl-D-glucamine and procaine.
The base-addition salts of acidic compounds according to the
invention are prepared by bringing the free acid form into contact
with a sufficient amount of the desired base, causing the formation
of the salt in a conventional manner. The free acid can be
regenerated by bringing the salt form into contact with an acid and
isolating the free acid in a conventional manner. The free acid
forms differ in a certain respect from the corresponding salt forms
thereof with respect to certain physical properties, such as
solubility in polar solvents; for the purposes of the invention,
however, the salts otherwise correspond to the respective free acid
forms thereof.
If a compound according to the invention contains more than one
group which is capable of forming pharmaceutically acceptable salts
of this type, the invention also encompasses multiple salts.
Typical multiple salt forms include, for example, bitartrate,
diacetate, difumarate, dimeglumine, diphosphate, disodium and
trihydrochloride, but this is not intended to represent a
restriction.
With regard to that stated above, it can be seen that the
expression "pharmaceutically acceptable salt" in the present
connection is taken to mean an active ingredient which comprises a
compound of the formula I in the form of one of its salts, in
particular if this salt form imparts improved pharmacokinetic
properties on the active ingredient compared with the free form of
the active ingredient or any other salt form of the active
ingredient used earlier. The pharmaceutically acceptable salt form
of the active ingredient can also provide this active ingredient
for the first time with a desired pharmacokinetic property which it
did not have earlier and can even have a positive influence on the
pharmacodynamics of this active ingredient with respect to its
therapeutic efficacy in the body.
The invention furthermore relates to medicaments comprising at
least one compound of the formula I and/or pharmaceutically usable
derivatives, solvates and stereoisomers thereof, including mixtures
thereof in all ratios, and optionally excipients and/or
adjuvants.
Pharmaceutical formulations can be administered in the form of
dosage units which comprise a predetermined amount of active
ingredient per dosage unit. Such a unit can comprise, for example,
0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5
mg to 100 mg, of a compound according to the invention, depending
on the condition treated, the method of administration and the age,
weight and condition of the patient, or pharmaceutical formulations
can be administered in the form of dosage units which comprise a
predetermined amount of active ingredient per dosage unit.
Preferred dosage unit formulations are those which comprise a daily
dose or part-dose, as indicated above, or a corresponding fraction
thereof of an active ingredient. Furthermore, pharmaceutical
formulations of this type can be prepared using a process which is
generally known in the pharmaceutical art.
Pharmaceutical formulations can be adapted for administration via
any desired suitable method, for example by oral (including buccal
or sublingual), rectal, nasal, topical (including buccal,
sublingual or transdermal), vaginal or parenteral (including
subcutaneous, intramuscular, intravenous or intradermal) methods.
Such formulations can be prepared using all processes known in the
pharmaceutical art by, for example, combining the active ingredient
with the excipient(s) or adjuvant(s).
Pharmaceutical formulations adapted for oral administration can be
administered as separate units, such as, for example, capsules or
tablets; powders or granules; solutions or suspensions in aqueous
or non-aqueous liquids; edible foams or foam foods; or oil-in-water
liquid emulsions or water-in-oil liquid emulsions.
Thus, for example, in the case of oral administration in the form
of a tablet or capsule, the active-ingredient component can be
combined with an oral, non-toxic and pharmaceutically acceptable
inert excipient, such as, for example, ethanol, glycerol, water and
the like. Powders are prepared by comminuting the compound to a
suitable fine size and mixing it with a pharmaceutical excipient
comminuted in a similar manner, such as, for example, an edible
carbohydrate, such as, for example, starch or mannitol. A flavour,
preservative, dispersant and dye may likewise be present,
Capsules are produced by preparing a powder mixture as described
above and filling shaped gelatine shells therewith. Glidants and
lubricants, such as, for example, highly disperse silicic acid,
talc, magnesium stearate, calcium stearate or polyethylene glycol
in solid form, can be added to the powder mixture before the
filling operation. A disintegrant or solubiliser, such as, for
example, agar-agar, calcium carbonate or sodium carbonate, can
likewise be added in order to improve the availability of the
medicament after the capsule has been taken.
In addition, if desired or necessary, suitable binders, lubricants
and disintegrants as well as dyes can likewise be incorporated into
the mixture. Suitable binders include starch, gelatine, natural
sugars, such as, for example, glucose or beta-lactose, sweeteners
made from maize, natural and synthetic rubber, such as, for
example, acacia, tragacanth or sodium alginate,
carboxymethyl-cellulose, polyethylene glycol, waxes, and the like.
The lubricants used in these dosage forms include sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. The disintegrants include,
without being restricted thereto, starch, methylcellulose, agar,
bentonite, xanthan gum and the like. The tablets are formulated by,
for example, preparing a powder mixture, granulating or
dry-pressing the mixture, adding a lubricant and a disintegrant and
pressing the entire mixture to give tablets. A powder mixture is
prepared by mixing the compound comminuted in a suitable manner
with a diluent or a base, as described above, and optionally with a
binder, such as, for example, carboxymethylcellulose, an alginate,
gelatine or polyvinylpyrrolidone, a dissolution retardant, such as,
for example, paraffin, an absorption accelerator, such as, for
example, a quaternary salt, and/or an absorbent, such as, for
example, bentonite, kaolin or dicalcium phosphate. The powder
mixture can be granulated by wetting it with a binder, such as, for
example, syrup, starch paste, acadia mucilage or solutions of
cellulose or polymer materials and pressing it through a sieve. As
an alternative to granulation, the powder mixture can be run
through a tableting machine, giving lumps of non-uniform shape,
which are broken up to form granules. The granules can be
lubricated by addition of stearic acid, a stearate salt, talc or
mineral oil in order to prevent sticking to the tablet casting
moulds. The lubricated mixture is then pressed to give tablets. The
compounds according to the invention can also be combined with a
free-flowing inert excipient and then pressed directly to give
tablets without carrying out the granulation or dry-pressing steps.
A transparent or opaque protective layer consisting of a shellac
sealing layer, a layer of sugar or polymer material and a gloss
layer of wax may be present. Dyes can be added to these coatings in
order to be able to differentiate between different dosage
units.
Oral liquids, such as, for example, solution, syrups and elixirs,
can be prepared in the form of dosage units so that a given
quantity comprises a pre-specified amount of the compound. Syrups
can be prepared by dissolving the compound in an aqueous solution
with a suitable flavour, while elixirs are prepared using a
non-toxic alcoholic vehicle. Suspensions can be formulated by
dispersion of the compound in a non-toxic vehicle. Solubilisers and
emulsifiers, such as, for example, ethoxylated isostearyl alcohols
and polyoxyethylene sorbitol ethers, preservatives, flavour
additives, such as, for example, peppermint oil or natural
sweeteners or saccharin, or other artificial sweeteners and the
like, can likewise be added.
The dosage unit formulations for oral administration can, if
desired, be encapsulated in microcapsules. The formulation can also
be prepared in such a way that the release is extended or retarded,
such as, for example, by coating or embedding of particulate
material in polymers, wax and the like.
The compounds of the formula I and salts, solvates and
physiologically functional derivatives thereof can also be
administered in the form of liposome delivery systems, such as, for
example, small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from various
phospholipids, such as, for example, cholesterol, stearylamine or
phosphatidylcholines.
The compounds of the formula I and the Salts, solvates and
physiologically functional derivatives thereof can also be
delivered using monoclonal anti-bodies as individual carriers to
which the compound molecules are coupled. The compounds can also be
coupled to soluble polymers as targeted medicament carriers. Such
polymers may encompass polyvinylpyrrolidone, pyran co-polymer,
polyhydroxypropylmethacrylamidophenol,
polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,
substituted by palmitoyl radicals. The compounds may furthermore be
coupled to a class of biodegradable polymers which are suitable for
achieving controlled release of a medicament, for example
polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric
acid, polyorthoesters, polyacetals, polydihydroxypyrans,
polycyanoacrylates and crosslinked or amphipathic block copolymers
of hydrogels.
Pharmaceutical formulations adapted for transdermal administration
can be administered as independent plasters for extended, close
contact with the epidermis of the recipient. Thus, for example, the
active ingredient can be delivered from the plaster by
iontophoresis, as described in general terms in Pharmaceutical
Research, 3(6), 318 (1986).
Pharmaceutical compounds adapted for topical administration can be
formulated as ointments, creams, suspensions, lotions, powders,
solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissue, for example
mouth and skin, the formulations are preferably applied as topical
ointment or cream. In the case of formulation to give an ointment,
the active ingredient can be employed either with a paraffinic or a
water-miscible cream base. Alternatively, the active ingredient can
be formulated to give a cream with an oil-in-water cream base or a
water-in-oil base.
Pharmaceutical formulations adapted for topical application to the
eye include eye drops, in which the active ingredient is dissolved
or suspended in a suitable carrier, in particular an aqueous
solvent.
Pharmaceutical formulations adapted for topical application in the
mouth encompass lozenges, pastilles and mouthwashes.
Pharmaceutical formulations adapted for rectal administration can
be administered in the form of suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration in
which the carrier substance is a solid comprise a coarse powder
having a particle size, for example, in the range 20-500 microns,
which is administered in the manner in which snuff is taken, i.e.
by rapid inhalation via the nasal passages from a container
containing the powder held close to the nose. Suitable formulations
for administration as nasal spray or nose drops with a liquid as
carrier substance encompass active-ingredient solutions in water or
oil.
Pharmaceutical formulations adapted for administration by
inhalation encompass finely particulate dusts or mists, which can
be generated by various types of pressurised dispensers with
aerosols, nebulisers or insufflators.
Pharmaceutical formulations adapted for vaginal administration can
be administered as pessaries, tampons, creams, gels, pastes, foams
or spray formulations.
Pharmaceutical formulations adapted for parenteral administration
include aqueous and non-aqueous sterile injection solutions
comprising antioxidants, buffers, bacteriostatics and solutes, by
means of which the formulation is rendered isotonic with the blood
of the recipient to be treated; and aqueous and non-aqueous sterile
suspensions, which may comprise suspension media and thickeners.
The formulations can be administered in single-dose or multidose
containers, for example sealed ampoules and vials, and stored in
freeze-dried (lyophilised) state, so that only the addition of the
sterile carrier liquid, for example water for injection purposes,
immediately before use is necessary. Injection solutions and
suspensions prepared in accordance with the recipe can be prepared
from sterile powders, granules and tablets.
It goes without saying that, in addition to the above particularly
mentioned constituents, the formulations may also comprise other
agents usual in the art with respect to the particular type of
formulation; thus, for example, formulations which are suitable for
oral administration may comprise flavours.
A therapeutically effective amount of a compound of the formula I
depends on a number of factors, including, for example, the age and
weight of the animal, the precise condition that requires
treatment, and its severity, the nature of the formulation and the
method of administration, and is ultimately determined by the
treating doctor or vet. However, an effective amount of a compound
according to the invention for the treatment of neoplastic growth,
for example colon or breast carcinoma, is generally in the range
from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per
day and particularly typically in the range from 1 to 10 mg/kg of
body weight per day. Thus, the actual amount per day for an adult
mammal weighing 70 kg is usually between 70 and 700 mg, where this
amount can be administered as a single dose per day or usually in a
series of part-doses (such as, for example, two, three, four, five
or six) per day, so that the total daily dose is the same. An
effective amount of a salt thereof can be determined as the
fraction of the effective amount of the compound according to the
invention per se. It can be assumed that similar doses are suitable
for the treatment of other conditions mentioned above.
The invention furthermore relates to medicaments comprising at
least one compound of the formula I and/or pharmaceutically usable
salts and stereo-isomers thereof, including mixtures thereof in all
ratios, and at least one further medicament active ingredient.
The invention also relates to a set (kit) consisting of separate
packs of (a) an effective amount of a compound of the formula I
and/or pharmaceutically usable salts and stereoisomers thereof,
including mixtures thereof in all ratios, and (b) an effective
amount of a further medicament active ingredient
The set comprises suitable containers, such as boxes, individual
bottles, bags or ampoules. The set may, for example, comprise
separate ampoules, each containing an effective amount of a
compound of the formula I and/or pharmaceutically usable salts and
stereoisomers thereof, including mixtures thereof in all
ratios,
and an effective amount of a further medicament active ingredient
in dissolved or lyophilised form.
Use
The present compounds are suitable as pharmaceutical active
ingredients for mammals, especially for humans, in the treatment
and control of diseases. These diseases include the proliferation
of tumour cells, pathological neovascularisation (or angiogenesis),
which promotes the growth of solid tumours, neovascularisation in
the eye (diabetic retinopathy, age-induced macular degeneration and
the like) and inflammation (psoriasis, rheumatoid arthritis and the
like), and proliferative diseases of the mesangial cells.
The present invention encompasses the use of the compounds of the
formula I and/or physiologically acceptable salts and solvates
thereof for the preparation of a medicament for the treatment or
prevention of tumours, tumour diseases and/or tumour
metastases.
The tumour disease is preferably selected from the group tumour of
the squamous epithelium, the bladder, the stomach, the kidneys, of
head and neck, the esophagus, the cervix, the thyroid, the
intestine, the liver, the brain, the prostate, the urogenital
tract, the lymphatic system, the stomach, the larynx, the lung, the
skin, monocytic leukaemia, lung adenocarcinoma, small-cell lung
carcinoma, pancreatic cancer, glioblastoma, breast carcinoma, acute
myeloid leukaemia; chronic myeloid leukaemia, acute lymphatic
leukaemia, chronic lymphatic leukaemia, Hodgkin's lymphoma,
non-Hodgkin's lymphoma.
Likewise encompassed is the use of the compounds according to claim
1 according to the invention and/or physiologically acceptable
salts and solvates thereof for the preparation of a medicament for
the treatment of osteoporosis, diabetes and obesity.
Likewise encompassed is the use of the compounds according to claim
1 according to the invention and/or physiologically acceptable
salts and solvates thereof for the preparation of a medicament for
the treatment or prevention of a disease in which angiogenesis is
involved.
A disease of this type in which angiogenesis is involved is an eye
disease, such as retina vascularisation, diabetic retinopathy,
age-induced macular degeneration and the like.
The angiogenic disease is preferably selected from the group
diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's
sarcoma, haemangioma, myocardial angiogenesis, atherosclerotic
plaque neovascularisation, angiogenic eye diseases, choroidal
neovascularisation, retrolental fibroplasia, macular degeneration,
corneal transplant rejection, rubeosis iridis, neuroscular
glaucoma, Oster Webber syndrome.
The proliferative disease of the mesangial cells is preferably
selected from the group glomerulonephritis, diabetic nephropathy,
malignant nephrosclerosis, thrombotic microangiopathy syndrome,
transplant rejection, glomerulopathy.
The use of compounds of the formula I and/or physiologically
acceptable salts and solvates thereof for the preparation of a
medicament for the treatment or prevention of inflammatory diseases
likewise falls within the scope of the present invention. Examples
of such inflammatory diseases include rheumatoid arthritis,
psoriasis, contact dermatitis, delayed hypersensitivity reaction
and the like.
The inflammatory disease is preferably selected from the group
Inflammatory bowel disease, arthritis, atherosclerosis, asthma,
allergies, inflammatory kidney diseases, multiple sclerosis,
chronic obstructive pulmonary disease, inflammatory skin diseases,
pardontal diseases, psoriasis, T-cell-promoted immune disease.
The inflammatory bowel disease is preferably selected from the
group ulcerative colitis, Crohn's disease non-specific colitis.
The T-cell-promoted immune disease is preferably selected from the
group allergic encephalomyelitis, allergic neuritis, transplant
rejection, graft-versus-host reaction, myocarditis, thyroiditis,
nephritis, systemic lupus erythematosus, insulin-dependent diabetes
mellitus.
The arthritis disease is preferably selected from the group
rheumatoid arthritis, osteoarthritis, Caplan's syndrome, Felty's
syndrome, Sjogren's syndrome, spondylitis ankylosans, Still's
disease, chondrocalcinosis, metabolic arthritis, rheumatic fever,
Reiter's disease, Wissler's syndrome.
The inflammatory kidney disease is preferably selected from the
group glomerulonephritis, glomerular injury, nephrotic syndrome,
interstitial nephritis, lupus nephritis, Goodpasture's syndrome,
Wegener's granulomatosis, renal vascolitis, IgA nephropathy,
idiopatic glomerular disease.
The inflammatory skin disease is preferably selected from the group
psoriasis, atopic dermatitis, contact sensitivity, acne.
Likewise encompassed is the use of the compounds of the formula I
and/or physiologically acceptable salts and solvates thereof for
the preparation of a medicament for the treatment or prevention of
a disease or condition in a mammal, in which to this method a
therapeutically effective amount of a compound according to the
invention is administered to a sick mammal in need of such
treatment. The therapeutic amount varies according to the specific
disease and can be determined by the person skilled in the art
without undue effort.
The present invention also encompasses the use compounds of the
formula I and/or physiologically acceptable salts and solvates
thereof for the preparation of a medicament for the treatment or
prevention of retinal vascularisation.
Likewise encompassed is the use of the compounds of the formula I
and/or physiologically acceptable salts thereof for the preparation
of a medicament for the treatment and/or combating of a
tumour-induced disease in a mammal, in which to this method a
therapeutically effective amount of a compound according to the
invention is administered to a sick mammal in need of such
treatment. The therapeutic amount varies according to the specific
disease and can be determined by the person skilled in the art
without undue effort.
The disclosed compounds of the formula I can be administered in
combination with other therapeutic agents, including anticancer
agents. As used here, the term "anticancer agent" relates to any
agent which is administered to a patient with cancer for the
purposes of treating the cancer.
The compounds of the formula I may also be administered together
with other well-known therapeutic agents that are selected for
their particular suitability for the condition being treated.
The present compounds are also suitable for combination with known
anti-cancer agents. These known anti-cancer agents include the
following: oestrogen receptor modulators, androgen receptor
modulators, retinoid receptor modulators, cytotoxic agents,
antiproliferative agents, prenyl-protein transferase inhibitors,
HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse
transcriptase inhibitors and further angiogenesis inhibitors. The
present compounds are particularly suitable for administration at
the same time as radiotherapy.
"Oestrogen receptor modulators" refers to compounds which interfere
with or inhibit the binding of oestrogen to the receptor,
regardless of mechanism. Examples of oestrogen receptor modulators
include, but are not limited to, tamoxifen, raloxifene, idoxifene,
LY353381, LY 117081, toremifene, fulvestrant,
4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]p-
henyl]-2H-1-benzopyran-3-yl]phenyl 2,2-dimethylpropanoate,
4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and
SH646.
"Androgen receptor modulators" refers to compounds which interfere
with or inhibit the binding of androgens to the receptor,
regardless of mechanism. Examples of androgen receptor modulators
include finasteride and other 5.alpha.-reductase inhibitors,
nilutamide, flutamide, bicalutamide, liarozole and abiraterone
acetate.
"Retinoid receptor modulators" refers to compounds which interfere
with or inhibit the binding of retinoids to the receptor,
regardless of mechanism. Examples of such retinoid receptor
modulators include bexarotene, tretinoin, 13-cis-retinoic acid,
9-cis-retinoic acid, .alpha.-difluoromethylornithine, ILX23-7553,
trans-N-(4'-hydroxyphenyl)retinamide and
N-4-carboxyphenylretinamide.
"Cytotoxic agents" refers to compounds which result in cell death
primarily through direct action on the cellular function or inhibit
or interfere with cell myosis, including alkylating agents, tumour
necrosis factors, intercalators, microtubulin inhibitors and
topoisomerase inhibitors.
Examples of cytotoxic agents include, but are not limited to,
tirapazimine, sertenef, cachectin, ifosfamide, tasonermin,
lonidamine, carboplatin, altretamine, prednimustine,
dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin,
temozolomide, heptaplatin, estramustine, improsulfan tosylate,
trofosfamide, nimustine, dibrospidium chloride, pumitepa,
lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,
dexifosfamide, cis-aminedichloro(2-methylpyridine)platinum,
benzylguanine, glufosfamide, GPX100,
(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamineplatinum(II)]bi-
s-[diamine(chloro)platinum(II)] tetrachloride,
diarisidinylspermine, arsenic trioxide,
1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine,
zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone,
pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,
3'-deamino-3'-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,
galarubicin, elinafide, MEN10755 and
4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin
(see WO 00/50032).
Examples of microtubulin inhibitors include paclitaxel, vindesine
sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine,
docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin,
cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,
anhydrovinblastine,
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyla-
mide, TDX258 and BMS188797. Topoisomerase inhibitors are, for
example, topotecan, hycaptamine, irinotecan, rubitecan,
6-ethoxypropionyl-3',4'-O-exobenzylidenechartreusin,
9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-k]acridine-2-(6H)propanamine-
,
1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]-
-pyrano[3',4':b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione,
lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,
BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate,
teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxyetoposide, GL331,
N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazo-
le-1-carboxamide, asulacrine,
(5a,5aB,Baa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[-
4-hydroxy-3,5-dimethoxy-phenyl]-5,5a,6,8,8a,9-hexohydrofuro(3',4':6,7)naph-
tho(2,3-d)-1,3-dioxol-6-one,
2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium-
, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,
5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-py-
razolo-[4,5,1-de]acridin-6-one,
N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethy-
l]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,
6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]-quinolin-7-o-
ne and dimesna.
"Antiproliferative agents" include antisense RNA and DNA
oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and
INX3001 and anti-metabolites such as enocitabine, carmofur,
tegafur, pentostatin, doxifluridine, trimeterxate, fludarabine,
capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium
hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin,
decitabine, nolatrexed, pemeterxed, nelzarabine,
2'-deoxy-2'-methylidenecytidine,
2'-fluoromethylene-2'-deoxycytidine,
N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea,
N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycyl-amino]-L-glycero-B-L-
-mannoheptopyranosyl]adenine, aplidine, ecteinascidin,
troxacitabine,
4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-
-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin,
5-fluorouracil, alanosine,
11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetr-
acyclo(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylacetic acid ester,
swainsonine, lometerxol, dexrazoxane, methioninase,
2'-cyano-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and
3-aminopyridine-2-carboxaldehyde thiosemicarbazone.
"Antiproliferative agents" also include monoclonal antibodies to
growth factors other than those listed under "angiogenesis
inhibitors", such as trastuzumab, and tumour suppressor genes, such
as p53, which can be delivered via recombinant virus-mediated gene
transfer (see U.S. Pat. No. 6,069,134, for example).
Evidence of the Action of Pharmacological Inhibitors on the
Proliferation/Vitality of Tumour Cells In Vitro
1.0 Background
In the present experiment description, the inhibition of tumour
cell proliferation/tumour cell vitality by active ingredients is
described.
The cells are sown in a suitable cell density in microtitre plates
(96-well format) and the test substances are added in the form of a
concentration series. After four further days of cultivation in
serum-containing medium, the tumour cell proliferation/tumour cell
vitality can be determined by means of an Alamar Blue test
system.
2.0 Experimental Procedure
2.1 Cell Culture
For example commercially available colon carcinoma cell lines,
ovary cell lines, prostate cell lines or breast cell lines,
etc.
The cells are cultivated in medium. At intervals of several days,
the cells are detached from the culture dishes with the aid of
trypsin solution and sown in suitable dilution in fresh medium. The
cells are cultivated at 37.degree. Celsius and 10% CO.sub.2.
2.2. Sowing of the Cells
A defined number of cells (for example 2000 cells) per culture/well
in a volume of 180 .mu.l of culture medium are sown in microtitre
plates (96 well cell-culture plates) using a multichannel pipette.
The cells are subsequently cultivated in a CO2 incubator
(37.degree. C. and 10% CO2).
2.3. Addition of the Test Substances
The test substances are dissolved, for example, in DMSO and
subsequently employed in corresponding concentration (if desired in
a dilution series) in the cell culture medium. The dilution steps
can be adapted depending on the efficiency of the active
ingredients and the desired spread of the concentrations. Cell
culture medium is added to the test substances in corresponding
concentrations. The addition of the test substances to the cells
can take place on the same day as the sowing of the cells. To this
end, in each case 20 .mu.l of substance solution from the
predilution plate are added to the cultures/wells. The cells are
cultivated for a further 4 days at 37.degree. Celsius and 10%
CO.sub.2.
2.4. Measurement of the Colour Reaction
In each case, 20 .mu.l of Alamar Blue reagent are added per well,
and the microtitre plates are incubated, for example, for a further
seven hours in a CO2 incubator (at 37.degree. C. and 10% CO.sub.2).
The plates are measured in a reader with a fluorescence filter at a
wavelength of 540 nm. The plates can be shaken gently immediately
before the measurement.
3. Evaluation
The absorbance value of the medium control (no cells and test
substances used) is subtracted from all other absorbance values.
The controls (cells without test substance) are set equal to 100
percent, and all other absorbance values are set in relation
thereto (for example in % of control):
Calculation:
.times..times..times..times..times..times..times..times..times..times..ti-
mes..times..times..times..times..times..times..times..times..times..times.-
.times..times..times..times..times..times..times. ##EQU00001##
IC.sub.50 values (50% inhibition) are determined with the aid of
statistics programs, such as, for example, RS1.
IC.sub.50 data for compounds according to the invention are shown
in Table
TABLE-US-00001 Material Order No. Manufacturer Microtitre plates
for cell culture 167008 Nunc (Nunclon Surface 96-well plate) DMEM
P04-03550 Pan Biotech PBS (10x) Dulbecco 14200-067 Gibco 96-well
plates (polypropylene) 267334 Nunc AlamarBlue .TM. BUF012B Serotec
FCS 1302 Pan Biotech GmbH Trypsin/EDTA solution 10x L 2153 Biochrom
AG 75 cm.sup.2 culture bottles 353136 BD Falcon A2780 93112519
ECACC Colo205 CCL222 ATCC MCF7 HTB22 ATCC PC3 CRL-1435 ATCC
Determination of the Proliferation Inhibition by Inhibitors of
Methionine Aminopeptidase 2 in the BrdU Proliferation Test
(Cellular Assay)
The inhibition of proliferation is determined by incorporation of
bromodesoxy-uridine (BrdU) into human umbilical vein endothelial
cells (HUVECs, Promo-Cell, C-12200). The HUVECs are cultivated at
37.degree. C. and 5% CO.sub.2 in basal medium (PromoCell, C-22200)
with supplement mix (PromoCell, C-39225).
After detachment of the cells by means of trypsin/EDTA, the number
of living cells is determined, and the cells are sown in a density
of 1000 cells per cavity in a total volume of 175 .mu.l (cavities
are coated in advance either with supplemented culture medium for
1-2 hours at 37.degree. C. or with 1.5% gelatine for 0.5-2 hours at
37.degree. C.). After cultivation for 24 hours, the test substances
are added in various concentrations (for example final
concentrations 30 .mu.M to 0.03 nM in 10-fold dilution steps) and a
volume of 25 .mu.l. The DMSO concentration is kept constant at
0.3%. After cultivation for a total of 48 or 72 hours, 20 .mu.l of
bromo-desoxyuridine (Roche, # 11647229001 diluted 1:1000 in culture
medium, final concentration 10 .mu.M) are added, and cultivation is
continued for a further 20 to 24 hours. After incubation with test
substances for a total of 72 or 96 hours, the culture medium is
removed, and an immunohistochemical determination is carried out
for detection of BrdU incorporation (BrdU ELISA, Roche, #
11647229001). To this end, the cells are treated with a fixative
for 30 min at room temperature and subsequently incubated with a
peroxidase-labelled anti-BrdU antibody (diluted 1:100 in antibody
dilution buffer) for 60 min at room temperature. After washing
three times with 1-fold-concentrated DPBS buffer (Gibco, # 14200),
the enzymatic reaction is initiated in TMB substrate solution. The
colour development is stopped after 15 min by addition of 25 .mu.l
of a 1M sulfuric acid solution. A determination of the optical
density is carried out within 0.5 min by measurement at a
wavelength of 450 nM. The controls used are cavities containing
DMSO-treated cells (100% control) or empty cavities (blank value).
The sensitivity of this test to inhibitors of methionine
aminopeptidase is checked and confirmed using the inhibitor
fumagillin.
MetAP-2 Activity Measurement
The MetAP-2 activity is determined by coupling enzymatic reactions.
The .sub.tripeptide Met-Arg-Ser (MAS) is employed as substrate. The
methionine liberated is firstly converted into Met.sub.ox and
H.sub.2O.sub.2 by L-aminooxidase (AAO). In the second step, the
peroxidase (POD) with the aid of the H.sub.2O.sub.2 catalyses the
oxidation of the leukodye dianisidine to dianisidine.sub.ox, the
increase of which is detected photometrically at 450 nm.
MetAP-2 activity can be recorded continuously as kinetics. The
reaction scheme illustrates that one mol of dianisidine.sub.ox is
formed per mol of methionene. The MetAP-2 enzyme activity can
therefore be calculated directly as .DELTA. absorption per time
unit. Qualification of the MetAP-2 activity (mol of Met/time unit)
is possible with the aid of the dianisidine.sub.ox extinction
coefficient.
The change in extinction per time unit is depicted graphically and
a slope calculation is carried out in the visually linear region of
the reaction.
Solubility Measurement
Determination by Shake Flask Solubility Measurement
Eluent Preparation:
Eluent A: 2 ml of diethylamine, for synthesis+1000 ml of methanol,
LiChrosolv Eluent B: 5 g of ammonium acetate, for analysis+5 ml of
methanol, LiChrosolv+995 ml of ultrapure water Sample Solvent:
Buffer: 3.954 g of sodium dihydrogenphosphate monohydrate+6.024 g
of sodium chloride+950 ml of ultrapure water the pH is adjusted
using 0.1 M NaOH or 0.1 M HCl.
Sample Preparation:
The samples are shaken at 37.degree. C. and 450 rpm for 24 h.
After about 7 h, the pH of the samples is checked and adjusted if
necessary. It is also checked whether the sample is still present
in excess.
Just before the end of the 24 h shaking time, the samples are again
checked for pH and a precipitate.
Ultrapure water unit: MilliQ gradient, Millipore, instrument:
F3PN37462D
Shaker: TiMix control, Buhler
Incubation hood: TH 15 Buhler
pH meter: 766 Calimatic Knick instrument: pH 1
pH electrode: InLab 423 Mettler
Results:
The compound
(2-morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]n-
aphthalen-1-ylmethyl}amine exhibits good solubility (283 g/ml) in
buffer system at pH 7, which influences its use in an orally
administered formulation particularly positively. Further Results:
Morpholin-4-yl-(4-{2-[(S)-1-(9H-purin-6-yl)pyrrolidin-2-yl]ethyl}naphthal-
en-1-yl)-methanone: 108 .mu.g/ml;
N-(2-hydroxypropyl)-4-[(R)-1-(9H-purin-6-yl)pyrolidin-2-ylmethoxy]quinoli-
ne-2-carboxamide: 325 .mu.g/ml;
N-methyl-2-[1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dih-
ydro-1H-naphthalen-(2Z)-ylidene]acetamide: 29 .mu.g/ml;
[1-oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-nap-
hthalen-(2Z)-ylidene]acetic acid: >3.8 mg/ml.
The compound
6-[(R)-2-(2,3-dichlorophenoxymethyl)pyrrolidin-yl]-9H-purine
disclosed in WO 2007/01.7069 exhibits a solubility of <1
.mu.g/ml.
APCI-MS (atmospheric pressure chemical ionisation--mass
spectrometry) (M+H).sup.+.
*Method information:
Column: Chromolith SpeedROD RP-18e 50-4.6 mm
Solvent A: water+0.1% of TFA
Solvent B: acetonitrile+0.1% of TFA
Flow rate: 2.4 ml/min
Gradient: 0.0 min 4% of B
2.6 min 100% of B
**HPLC: La Chrom unit
Chromolite Performance RP18-e 100-4.6 mm
Gradient: ACN/H2O comprising 0.01% of formic acid
Method: chromolith/chromolith (extended)
Flow rate: 3 ml/min
$ Agilent unit
Chromolite Performance RP18-e 50-4.6 mm
Gradient: ACN/H2O comprising 0.04/0.05% of formic acid
Method: polar
Flow rate: 2.4 ml/min
The NMR spectra are recorded in DMSO-d.sub.6 and in
DMSO-d.sub.6+TFA-d.sub.1. The data indicated relate to the
DMSO-d.sub.6 TFA-d.sub.1 spectra.
Above and below, all temperatures are indicated in .degree. C. In
the following examples, "conventional work-up" means: water is
added if necessary, the pH is adjusted, if necessary, to values
between 2 and 10, depending on the constitution of the end product,
the mixture is extracted with ethyl acetate or dichloromethane, the
phases are separated, the organic phase is dried over sodium
sulfate and evaporated, and the product is purified by
chromatography on silica gel and/or by crystallisation.
M.p.: melting point
Mass spectrometry (MS): EI (electron impact ionisation) M.sup.+ FAB
(fast atom bombardment) (M+H).sup.+ ESI (electrospray ionisation)
(M+H).sup.+
APCI-MS (atmospheric pressure chemical ionisation--mass
spectrometry) (M+H).sup.+,
EXAMPLES
Example 1
The preparation of
6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine
("A1") is carried out analogously to the following scheme
##STR00019##
1.1 83.7 g of D-proline are dissolved in 900 ml of tert-butanol,
and 151 ml of triethylamine are added. Di-tert-butyl dicarbonate is
dissolved in 300 ml of tert-butanol and added dropwise to the first
solution. After stirring at RT for 21 hours, the precipitate is
filtered off and washed with warm tert-butanol. The combined
filtrates are taken up in about 700 ml of diethyl ether and washed
with 500 ml of. 1 N HCl solution, 500 ml of saturated sodium
carbonate solution and 500 ml of sodium chloride solution. Further
work-up is carried out in the conventional manner, giving 86.7 g of
a colourless oil (corresponds to J. Org. Chem. 1988, 53 (3),
485).
1.2 12.3 g of lithium chloride are dissolved in 140 ml of ethanol
to form a clear solution and cooled to -20.degree. C. 11 g of
NaBH.sub.4 are likewise suspended in 140 ml of ethanol and added to
the cold lithium chloride solution. After 10 minutes, a solution of
29.7 g of 1-tert-butyl D-pyrrolidine-1,2-dicarboxylate in 140 ml of
THF is added at the temperature indicated, and the mixture is
allowed to warm to RT for 19 hours. For work-up, the reaction
mixture is cooled to 0.degree. C., and 300 ml of saturated citric
acid are carefully added. The organic phase is separated off, dried
over sodium sulfate and evaporated to dryness, giving 12.95 g of a
pale-yellow oil (corresponds to J. Org. Chem. 1993, 58 (5),
1213).
1.3 100 mg of tert-butyl 2-hydroxymethylpyrrolidine-1-carboxylate
are dissolved in 2 ml of dichloromethane, 1401 of triethylamine are
added, and 451 of methanesulfonyl chloride are subsequently added
dropwise. After stirring at RT for 45 minutes, the reaction
solution is diluted with a further 2 ml of dichloromethane and
washed successively with 4 ml of water, 4 ml of 10% citric acid and
4 ml of saturated sodium chloride solution. The organic phase is
dried over sodium sulfate, evaporated, and the 140 mg of crude
product obtained, Rt.: 1.904 min, is immediately reacted further in
the next step.
1.4 2 g of tert-butyl
2-methanesulfonyloxymethylpyrrolidine-1-carboxylate are suspended
in 50 ml of DMF together with 1.1 g of 1-naphthol and 3 g of
caesium carbonate and warmed at 80.degree. C. for 12 hours. (These
and alternative conditions are found in March, J. "Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure," 4th ed.; John
Wiley & Sons: New York, 1992, pp 430-431, and the references
cited therein.) For work-up, the reaction mixture is poured into 50
ml of dichloromethane and 50 ml of water. The organic phase is
dried and, after removal of the solvent, purified by chromatography
on silica gel, giving 1.25 g of a brown oil, which is reacted
further directly;
*Rt.: 2.96 min.
1.5 1.25 g of tert-butyl
2(-naphthalen-1-yloxymethyl)pyrrolidine-1-carboxylate are dissolved
in 10 ml of THF, and 5 ml of ethanolic hydrochloric acid are added.
The reaction mixture is stirred at 80.degree. C. for 6, and the
resultant precipitate is filtered off with suction, washed with THF
and reacted further directly in the following reaction; Rt.: 1.633
min; [M+H].sup.+ 228.
1.6 235 mg of 6-chloropurine, 400 mg of
2(-naphthalen-1-yloxymethyl)pyrrolidine and 0.8 ml of triethylamine
are dissolved in 30 ml of 1-butanol and irradiated in the microwave
at 120.degree. C. for 6 h. After removal of the solvent in vacuo,
the residue is taken up in 10 ml of methanol, the crystals which
precipitate in the process are filtered off with suction and washed
with methanol, giving 340 mg of colourless crystals
6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine
("A1"); Rt.: 1.806 min; [M+H].sup.+346; m.p. 207-208.degree.;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s,
1H), 8.25 (s, 1H), 8.12 (s, 2H), 7.87 (dd, 1H, J=2.0 Hz, J=7.1 Hz),
7.54-7.49 (m, 2H), 7.46 (d, 1H, J=8.2 Hz), 7.40-7.37 (m, 1H), 7.07
(m, 1H), 4.92 (dd, 1H, J=3.4 Hz, J=9.1 Hz), 4.27 (t, 1H, J=8.1 Hz),
2.25-2.07 (m, 4H).
Example 2
The preparation of
4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalene-1-carbaldehyde
("A2") is carried out analogously to the following scheme
##STR00020##
296 mg of 6-Cl-purine and 560 mg of
4-((R)-1-pyrrolidin-2-ylmethoxy)naphthalene-1-carbaldehyde are
warmed at 120.degree. C. in the microwave for 6 h together with 1.0
ml of N-ethyldiisopropylamine in 30 ml of 1-butanol. Conventional
aqueous work-up and chromatography on silica gel gives 100 mg of
4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalene-1-carbaldehyde
("A2") as colourless crystals; Rt: 1.729 min; [M+H].sup.+374.2;
m.p. 167-168.degree.;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.98 (br. s,
1H), 10.18 (s, 1H), 9.22 (d, 1H, J=8.3 Hz), 8.25 (m, 2H), 8.13 (m,
2H), 7.76 (ddd, 1H, J=1.3 HZ, J=6.9 Hz, J=8.3 HZ), 7.65 (t, 1H,
J=7.6 Hz), 7.37 (m, 1H), 4.68 (dd, 1H, J=3.4 Hz, J=9.3 Hz), 4.42
(t, 1H, J=8.0 Hz), 4.00 (m, 3H), 2.25 (m, 3H), 2.08 (m, 1H).
Example 3
Preparation of
6-[(R)-2-(4-morpholin-4-ylmethylnaphthalen-1-yloxymethyl)pyrrolidin-1-yl]-
-9H-purine ("A3")
##STR00021##
155 mg of 6-Cl-purine and 320 mg of
4-[4-((R))-1-pyrrolidin-2-ylmethoxy)-naphthalen-1-ylmethyl]morpholine
are warmed at 120.degree. C. in the microwave for 6 h together with
0.5 ml of N-ethyldiisopropylamine in 20 ml of 1-butanol. The
conventional work-up and purification protocol gives 4 mg of
6[(R)-2-(4-morpholin-4-ylmethylnaphthalen-1-yloxymethyl)pyrrolidin-1-yl]--
9H-purine as colourless crystals; * Rt.: 2.14 min; m.p.
134-138.degree.;
.sup.1H-NMR (500 MHz, d.sub.5-DMSO) .delta. [ppm] 12.97 (br. s,
1H), 8.23 (m, 1H), 8.20 (m, 2H), 8.11 (m, 2H), 7.53 (m, 2H), 7.28
(m, 1H), 6.98 (m, 1H), 4.90 (m, 1H), 4.48 (m, 1H), 4.25 (m, 2H),
3.75 (m, 3H), 3.51 (m, 3H), 2.24 (m, 2H), 2.06 (m, 1H), 1.09 (m,
1).
Example 4
The preparation of
6-[(R)-2-(4-butoxymethylnaphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-puri-
ne ("A4") is carried out analogously to Example 1
##STR00022##
Rt: 2.349 min; [M+H].sup.+432.2; m.p. 214-216'; .sup.1H-NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] 12.95 (br. s, 1H), 8.24 (s, 1H),
8.16 (br. s, 1H), 8.11 (s, 1H), 8.04 (d, 1H, J=8.3 Hz), 7.57 (dt,
1H, J=1.5 Hz, J=6.8 Hz), 7.52 (dt, 1H, J=0.9 Hz, J=8.2. Hz), 7.37
(d, 1H, J=7.8 Hz), 5.46 (br. m, 1H), 4.77 (s, 2H), 4.51 (dd, 1H,
J=3.2 Hz, J=9.2 Hz), 4.25 (t, 1H, J=8.1 Hz), 3.84 (br. m, 2H), 3.44
(t, 2H), 2.23 (br. m, 3H), 2.06 (br. m, 1H), 1.49 (m, 2H), 1.29 (m,
2H), 0.83 (t, 3H, J=7.4 Hz).
Example 5
Preparation of
6-{2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine ("A5")
##STR00023##
5.1 3 ml of 1-methylpyrroline are dissolved in 25 nil of THF and
deprotonated at -78.degree. C. for 30 minutes using 22.6 ml of BuLi
(1 M in hexane). 6.5 g of 2-chlorobenzyl bromide are dissolved in
25 ml of THF and added dropwise at the temperature indicated. After
30 minutes, the mixture is allowed to warm to RT for 12 hours. For
work-up, 50 ml of water are added, and the mixture is extracted to
exhaustion with dichloromethane. The combined organic phases are
dried over sodium sulfate, evaporated and purified by
chromatography on silica gel, giving 4.5 g of
5-[2-(2-chlorophenyl)ethyl]-3,4-dihydro-2H-pyrrole as a colourless
oil, which is employed in the next reaction; Rt.: 1.303 min;
[M+H].sup.+208.
5.2 4.5 g of 5-[2-(2-chlorophenyl)ethyl]-3,4-dihydro-2H-pyrrole are
dissolved in 150 ml of methanol, and 1.5 g of sodium
cyanoborohydride are added. Ethanolic hydrochloric acid is added at
0.degree. C. until a pH of 2 has been established. The reaction is
subsequently allowed to run at RT for 6 h, before the reaction
mixture is poured into 10 ml of concentrated hydrochloric acid and
diluted with water. The mixture is then neutralised using
concentrated sodium hydroxide solution, and the aqueous phase is
extracted with ethyl acetate. Drying over sodium sulfate and
evaporation gives 1 g of colourless oil, which is immediately
reacted further; Rt.: 1.486 min; [M+H].sup.+210.
5.3 500 ring of 2-[2-(2-chlorophenyl)ethyl]pyrrolidine, 367 mg of
6-chloro-purine and 0.6 ml of triethylamine are dissolved in 40 ml
of 1-butanol and reacted at 120.degree. C. in the microwave for 6
h. After removal of the solvent in vacuo, the residue is taken up
in 50 ml of ethyl acetate and 50 ml of water, the organic phase is
dried, evaporated and recrystallised from ether, giving. 500 mg of
beige crystals of racemic
6-{-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine ("A5");
Rt.: 1.793 min; [M+H].sup.+328;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.91 (br. s,
1H), 8.18 (s, 1H), 8.09 (s, 2H), 7.40-7.35 (m, 2H), 7.28-7.19 (m,
2H), 2.79 (m, 2H), 2.12 (m, 6H), 1.70 (m, 1H).
110 mg of the racemate
6-{-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine are
dissolved in 7 ml of methanol and 2 ml of diethylamine and divided
into 9 vials. The solutions are separated by means of supercritical
CO.sub.2 (SFC) on Chiralcel OD-H using 5 ml/min of CO.sub.2+40% of
MOH0, 5 DEA, giving 46.6 mg of
6-{(R)-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine
("A5b") having an enantiomer ratio of 98.8%:1.2%.
and 45.3 mg of
6-{(S)-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine
("A5a") having an enantiomer ratio 0.4%:99.6%.
Example 6
Preparation of
morpholin-4-yl-(4-{2-[-1-(9H-purin-6-yl)pyrrolidin-2-yl]ethyl}naphthalen--
1-yl)methanone ("A6")
##STR00024## ##STR00025##
6.15 g of commercially available 4-methyl-1-naphthylic acid are
reacted with 4.7 ml of morpholine, 5.2 g of
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and
3.6 g of 1-hydroxybenzotriazole at RT for 12 h. Work-up and
purification gives 5.4 g of brown oil
(4-methylnaphthalen-1-yl)morphlin-4-ylmethanone; Rt.: 1.924 min;
[M+H].sup.+256.2.
6.2 5.4 g of (4-methylnaphthalen-1-yl)morpohlin-4-ylmethanone are
reacted with 4.3 g of N-bromosuccinimide and 100 mg of
.alpha.,.alpha.-azobisisobutyronitrile in 100 ml of dichloroethane
at 80.degree. C. for 10 h. Aqueous work-up and chromatography on
silica gel gives 4.5 g of a colourless oil
(4-bromomethylnaphthalen-1-yl)-morpholin-4-ylmethanone; Rt: 2.028
min; [M+H].sup.+334.01336.0.
6.3 1.4 ml of 2-methyl-1-pyrroline are dissolved in 50 ml of THF
and cooled to -78.degree. C. 11.3 ml of n-butyllithium (15% in
n-hexane) are then added dropwise. After stirring for 30 minutes,
the (4-bromomethylnaphthalen-1-yl)morpholin-4-ylmethanone dissolved
in 25 ml of THF is added, and the mixture is allowed to warm to RT
for 8 h. Conventional work-up and purification gives 2 g of yellow
oil
{4-[2-(4,5-dihydro-3H-pyrrol-2-yl)ethyl]naphthalen-1-yl)morpholin-4-ylmet-
hanone; Rt: 1.407 min; [M+H].sup.+337.2.
6.4 1 g of
{4-[2-(4,5-dihydro-3H-pyrrol-2-yl)ethyl]naphthalen-1-yl)morpholin-4-ylmet-
hanone is dissolved in 50 ml of methanol, and 0.26 g of sodium
cyano borohydride is added. A pH of 2 inset at 0.degree. C. using
methanolic HCl. The mixture is subsequently allowed to left to stir
at RT for a further 6 h and then subjected to aqueous work-up. A pH
of 9 is set using aqueous NaOH, and the mixture is extracted with
ethyl acetate. The dried and evaporated organic phase is purified
by chromatography, giving 460 mg of
morpholin-4-yl-[4-(2-pyrrolidin-2-ylethyl)naphthalen-1-yl]methanone;
Rt.: 1.420 min; [M+H].sup.+339.2.
6.5 231 mg of 6-Cl-purine are reacted with 460 mg of
morpholin-4-yl-[4-(2-pyrrolidin-2-ylethyl)naphthalen-1-yl]methanone
in N-ethyldiisopropylamine and 1-butanol in the microwave as
described. Conventional work-up and purification gives 210 mg of
"AS" as colourless crystals; Rt.: 1.606 min; [M+H].sup.+457.2; m.p.
158-160';
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.89 (br. s,
1H), 8.12 (s, 2H), 7.78 (d, 1H, J=8.2 Hz), 7.59 (m, 3H), 7.47 (d,
1H, J=7.0 Hz), 7.35 (d, 1H, J=7.1 Hz), 5.44 (m, 1H), 5.07 (br. m,
1H), 3.82 (m, 1H), 3.75 (m, 3H), 3.61 (m, 2H), 3.45 (m, 2H), 3.11
(m, 2H), 3.01 (m, 1H), 2.25 (m, 1H), 2.10 (m, 2H), 2.01 (m, 1H),
1.76 (m, 2H).
6.6 220 mg of the racemic mixture
morpholin-4-yl-(4-{2-[-1-(9H-purin-6-yl)-pyrrolidin-2-yl]ethyl}naphthalen-
-1-yl)methanone ("A6") are separated by SFC on a 1 cm Chiralcel
OD-H column.
The separation is carried out using a flow rate of 5 ml/min. The
liquid phase consists of 60% of liquid CO.sub.2 and 40% of a
mixture of 99.5% of methanol with 0.5% of diethylamine.
Fraction 1: m=120 mg enantiomer ratio: Ena 1 90.9%:9.1% Ena2;
Fraction 2: m=123 mg enantiomer ratio: Ena 1 12%:88% Ena2.
The two fractions were subsequently separated, each dissolved in
methanol and separated on a 1 cm Chiralcel OD-H column.
The separation is carried out using a flow rate of. 5 ml/min. The
liquid phase consists of 60% of liquid CO.sub.2 and 40% of a
mixture of 99.5% of methanol with 0.5% of diethylamine.
Fraction 1: m=64 mg enantiomerically pure:
morpholin-4-yl-(4-{2-[(S)-1-(9H-purin-6-yl)pyrrolidin-2-yl]ethyl}naphthal-
en-1-yl)-methanone ("A6a");
Fraction 2: m=73 mg enantiomerically pure:
morpholin-4-yl-(4-{2-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl]ethyl}naphthal-
en-1-yl)-methanone ("A6b").
Example 7
Preparation of
6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine
("A7")
##STR00026##
7.1 30 g of (2R,4R)-4-hydroxy pyrrolidine-2-carboxylic acid are
suspended in 200 ml of methanol and cooled to 0.degree. C. Thionyl
chloride (18.1 ml) is subsequently added dropwise at the same
temperature distributed over an hour. The reaction mixture (RM) is
warmed to room temperature (RT) over 12 h, during which a clear
solution forms. The solvent is removed in vacuo, and the residue
obtained is recrystallised from ether, giving 50 g of methyl
(2R,4R)-4-hydroxypyrrolidine-2-carboxylate; Rt.: 0.386 min;
[M+H].sup.+146.2.
7.2 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2-carboxylate, 64.2
ml of di-tert-butyl dicarbonate, 116.4 ml of triethylamine and 2.4
g of 4-(dimethylamino)pyridine are dissolved in 500 ml of
dichloromethane and stirred at RT for 12 h. The reaction mixture is
washed with water, and the organic phase is dried over magnesium
sulfate and evaporated. The residue is chromatographed over a
silica-gel column, giving 37 g of colourless crystals 1-tert-butyl
2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-carboxylate.
7.3 5 g of 1-tert-butyl 2-methyl
(2R,4R)-4-hydroxypyrrolidine-1,2-carboxylate is dissolved in 100 ml
of CH.sub.2Cl.sub.2 under an N.sub.2 atmosphere and cooled to
-78.degree. C. 3 ml of diethylaminosulfur trifluoride are
subsequently slowly added dropwise. The reaction mixture is warmed
to RT over 12 h. After aqueous work-up, the organic phase is dried
over magnesium sulfate, evaporated in vacuo, and the 5.3 g of oily
1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-carboxylate
obtained are reacted further in the next reaction without further
purification.
7.4 5.3 g of 1-tert-butyl 2-methyl
(2R,4S)-4-fluoropyrrolidine-1,2-carboxylate are dissolved in 100 ml
of THF and cooled to -20.degree. C. 1.2 g of LiBH.sub.4 are
subsequently added. The reaction mixture is then stirred at RT for
a further 6 h. The mixture is subjected to aqueous work-up, and the
3.2 g of tert-butyl
(2R,4S)-4-fluoro-2-hydroxymethylpyrrolidine-1-carboxylate obtained
are reacted further directly.
7.5 3.2 g of tert-butyl
(2R,4S)-4-fluoro-2-hydroxymethylpyrrolidine-1-carboxylate are
dissolved in 50 ml of CH.sub.2Cl.sub.2 with stirring, 3.1 ml of
triethylamine are added, the mixture is cooled to 0-5.degree. C.,
and a solution of 1.4 ml of methane-sulfonyl chloride in 10 ml of
CH.sub.2Cl.sub.2 is subsequently added dropwise. The mixture is
subsequently stirred at RT for 4 h. After aqueous work-up, the 4.1
g of tert-butyl
(2R,4S)-4-fluoro-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate)
obtained are reacted further directly.
7.6 2 g of test-butyl.
(2R,4S)-4-fluoro-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate,
0.9 ml of 2-chlorophenol and 3.6 g of caesium carbonate are
suspended in 60 ml of DMF and stirred at 80.degree. C. for 12 h.
After aqueous work-up, the 2.5 g of tert-butyl
(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine-1-carboxylate
obtained are reacted further directly.
7.7 2.5 g of tert-butyl
(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine-1-carboxylate
are dissolved in 20 ml of THF and stirred at 80.degree. C. for 2 h
with 5 ml of ethanolic hydrochloric acid. After basic work-up using
saturated sodium hydrogencarbonate solution, the organic phase is
subjected to conventional work-up, and the residue obtained is
purified by chromatography, giving 780 mg of
(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine as brown oil;
Rt.: 0.700 min; [M+H].sup.+230.2.
7.8 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine
and 525 mg of 6-chloropurine are irradiated at 120.degree. C. in
the microwave for 6 h together with 1.2 ml of
N-ethyldiisoproylamine and 40 ml of 1-butanol, during which a
pressure of 10 bar arises. After conventional aqueous work-up, the
residue obtained is crystallised from ether, giving 350 mg of
6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine
("A7") as beige crystals; Rt.: 1.790 min; [M+H].sup.+348.2; m.p.
143-144.degree.;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.07 (br. s,
1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.40 (dd, 1H, J=1.6 Hz, J=7.9 Hz),
7.25 (dt, 1H, J=1.2 Hz, J=7.9 Hz), 7.14 (m, 1H), 6.93 (dt, 1H,
J=1.4 Hz, J=7.7 Hz), 5.62 (dd, 1H, J=3.16 Hz, J=54.1 Hz), 4.99 (m,
1H), 4.49 (m, 1H), 4.36 (dd, 1H, J=2.5 Hz, J=9.5 Hz), 4.02-4.08 (m,
4H).
Example 8
Preparation of
6-[(R)-4,4-difluoro-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purin-
e ("A8")
##STR00027##
200 mg of
(R)-5-(naphthalen-1-yloxymethyl)-1-(9H-purin-6-yl)pyrrolidin-3--
one are dissolved in 20 ml of dichloromethane and cooled to
-78.degree. C. 0.18 ml of diethylaminosulfur trifluoride is then
added dropwise, and the mixture is allowed to warm to RT for 8 h.
Conventional work-up and purification gives 3 mg of "A8"; Rt.:
2.056; [M+H].sup.+3822.
Example 9
The Preparation of
(3-fluorophenyl)-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethyl]amine
("A9"),
(3-fluorophenyl)methyl-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethy-
]amine ("A10") and
6-{(R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidin-1-yl}-9H-purine
("A11") is carried out analogously to the following scheme
##STR00028##
A solution of 3 ml of DMSO in 100 ml of dichloromethane is cooled
to -78.degree. C. under protective gas, and 2.8 ml of oxalyl
chloride are added dropwise. After 10 min, 5 g of tert-butyl
2-hydroxymethylpyrrolidine-1-carboxylate, dissolved in 5 ml of
dichloromethane, are added dropwise. After 2 h, 10 ml of
triethylamine are slowly added at the temperature indicated, and
the batch is not cooled further. After about 2 h, the reaction
mixture has reached room temperature, and 10 ml of water are added.
After 30 min, the phases are separated, the organic phase is washed
again with water and, after drying over magnesium sulfate and
removal of the solvent in vacuo, is chromatographed on silica gel,
giving 3.8 g of a colourless oil tert-butyl
(R)-2-formylpyrrolidine-1-carboxylate.
Preparation of "A9"
2 g of tert-butyl (R)-2-formylpyrrolidine-1-carboxylate and 1.1 ml
of 3-fluoro-aniline are dissolved in 50 ml of 1,2-dichloroethane
and cooled to 0.degree. C. under a protective-gas atmosphere. 3.3 g
of sodium acetoxyborohydride (95%) are then introduced in portions.
After a reaction time of 12 h at RT, the batch is subjected to
aqueous work-up under standard conditions, and 3.7 g of a
colourless oil tert-butyl
(R)-2-[(3-fluorophenylamino)methyl]pyrrolidine-1-carboxylate are
employed in the next step without further purification.
1.7 g of tert-butyl
(R)-2-[(3-fluorophenylamino)methyl]pyrrolidine-1-carboxylate are
dissolved in 10 ml of THF, and 5 ml of ethanolic hydrochloric acid
are added. The mixture is stirred at 80.degree. C. for 4 h and, for
work-up, partitioned between 50 ml of water and 50 ml of ethyl
acetate at room temperature. Conventional work-up and purification
by chromatography on silica gel gives 400 mg of a pale-brown oil
(3-fluorophenyl)-(R)-1-pyrrolidin-2-ylmethylamine; Rt.: 1.291 min;
[M+H].sup.+195.2.
155 mg of 6-chloropurine and 200 mg of
(3-fluorophenyl)-(R)-1-pyrrolidin-2-yl-methylamine are dissolved in
40 ml of 1-butanol, and 0.3 ml of N-ethyldiisopropylamine is added.
The reaction mixture is irradiated at 120.degree. C. in the
microwave for 6 h, during which a pressure increase (.about.4 bar)
is noted. When the reaction is complete, the batch is freed from
volatile constituents in vacuo and chromatographed on silica gel,
giving 120 mg of "A9"; Rt.: 1.825 min; [M+H].sup.+420.2;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.94 (br. s,
1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.05 (q, 1H, J=7.7 Hz), 6.76 (d,
1H, J=12.4 Hz), 6.59 (dd, 1H, J=1.2 Hz, J=8.0 Hz), 6.29 (dt, 1H,
J=2.0 Hz, J=8.2 Hz), 4.57 (m, 1H), 4.22 (m, 1H), 3.94 (m, 1H), 3.49
(m, 1H), 3.00 (m, 1H), 2.06 (m , 2H), 1.96 (m, 2H).
Preparation of "A10":
2 g of tert-butyl
(R)-2-[(3-fluorophenylamino)methyl]pyrrolidine-1-carboxylate are
deprotonated using 360 mg of sodium hydride (60% in mineral oil) in
50 ml of THF for 30 min. 0.9 ml of iodomethane are subsequently
added, and the mixture is stirred at RT for 12 h. 0.9 g of
potassium carbonate and 7.9 ml of iodomethane are again added.
After 12 h at 50.degree. C., the batch is subjected to aqueous
work-up, giving 920 mg of tert-butyl
(R)-2-{[(3-fluorophenyl)methylamino]methyl}pyrrolidine-1-carboxylate,
which are reacted directly without further purification; Rt.: 2.499
min; [M+H].sup.+309.2.
920 mg of tert-butyl
(R)-2-{[(3-fluorophenyl)methylamino]methyl}pyrrolidine-1-carboxylate
are dissolved in, 10 ml of THF, and 5 ml of ethanolic hydrochloric
acid are added. The mixture is stirred at 80.degree. C. for 4 h
and, for work-up, partitioned between 50 ml of water and 50 ml of
ethyl acetate at room temperature. Conventional work-up and
purification by chromatography on silica gel gives 300 mg of
(3-fluorophenyl)methyl-(R)-1-pyrrolidin-2-ylmethylamine; Rt.: 1.377
min; [M+H].sup.+209.2.
232 mg of 6-chloropurine and 300 mg of
(3-fluorophenyl)methyl-(R)-1-pyrrolidin-2-ylmethylamine are
dissolved in 40 ml of 1-butanol, and 0.3 ml of
N-ethyldiisopropylamine is added. The reaction mixture is
irradiated at 120.degree. C. in the microwave for 0.6 h, during
which a pressure increase (.about.4 bar) is noted. When the
reaction is complete, the batch is freed from volatile constituents
in vacuo and chromatographed on silica gel, giving 250 mg of "MO"
(yellow crystals);
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s,
1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.19 (q, 1H, J=8.0 Hz), 7.05 (m,
1H), 6.82 (d, 1H, J=6.5 Hz), 6.38 (dt, 1H, J=2.0 Hz, J=8.2 Hz),
5.31 (m, 1H), 4.65 (m, 1H), 4.21 (m, 1H), 4.00 (m, 1H), 3.84 (m,
1H), 3.06 (s, 3H), 2.17 (m, 1H), 2.00 (m, 1H), 1.91 (m, 2H).
Preparation of "A11":
775 mg of commercially available diethyl 3-chlorobenzylphosphonate
are dissolved in 20 ml of THF, and 3 ml of lithium
hexamethyldisilazane are added dropwise at -78.degree. C. under
protective gas. After 1 h, a solution of 500 mg of
tert-butyl-(R)-2-formylpyrrolidine-1-carboxylate in 5 ml of THF is
added dropwise at the temperature indicated. The batch is stirred
at RT for 3 h and subsequently subjected to aqueous work-up, giving
1 g of tert-butyl
(R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine-1-carboxylate as
colourless oil, which is immediately reacted further.
1 g of tert-butyl
(R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine-1-carboxylate are
dissolved in 10 ml of THF, and 5 ml of ethanolic hydrochloric acid
are added. The mixture is stirred at 80.degree. C. for 4 h and, for
work-up, partitioned between 50 ml of water and 50 nil of ethyl
acetate at room temperature. Conventional work-up and purification
by chromatography on silica gel gives 750 mg of
(R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine; Rt.: 1.554 min;
[M+H].sup.+208.2.
695 mg of 6-chloropurine and 850 mg of
(R)-2-[(E)-2-(3-chlorophenyl)vinyl]-pyrrolidine are dissolved in 20
ml of 1-butanol and warmed at 130.degree. C. in the microwave for 6
h with 3.1 ml of triethylamine. For work-up, the batch is
partitioned between ethyl acetate and water, the organic phase is
dried over sodium sulfate, filtered off and evaporated in vacuo.
The residue is purified by chromatography, giving 220 mg of
6-[(R)-2-((E)-2-(3-chlorophenyl)vinyl)pyrrolidin-1-yl]-9H-purine
("A11"); Rt: 1.778 min; [M+H].sup.+326.2; m.p. 194-196.degree.;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.89 (br. S,
1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.46 (s, 1H), 7.34-7.22 (m, 3H),
6.54 (dd, 1H, J=4.9 Hz, J=15.9 Hz), 6.37 (d, 1H, J=15.9 Hz), 5.49
(m, 1H), 4.02 (m, 2H), 2.17 1.95, (m 4H).
Example 10
Preparation of
6-[(R)-2((E)-2-naphthalen-1-ylvinyl)pyrrolidin-1-yl]-9H-purine ("A
12")
##STR00029##
3.1 g of 6-Cl-purine and 3.6 g of
(R)-2-(E)-2-naphthalen-1-ylvinyl)pyrrolidine are warmed at
120.degree. C. in the microwave for 6 h with 6.8 ml of
N-ethyldiisopropylamine in 50 ml of 1-butanol. Conventional aqueous
work-up and purification by chromatography gives 1.8 g of
6-[(R)-2-(E)-2-naphthalen-1-ylvinyl)pyrrolidin-1-yl]-9H-purine
("A12") as colourless crystals;
Rt: 1.848 min; [M+H].sup.+342.2.
Example 11
Preparation of
7-[(R)-2-(2-chlorophenoxymethyl)pyrrolidin-1-yl]-1,2,5-thiadiazolo[3,4-b]-
pyridine ("A13")
##STR00030##
100 mg of 6-bromo-1,2,5-thiadiazolo[3,4-b]pyrimidine are warmed at
100.degree. C. for 12 h together with 402 mg of
(R)-2-(2-chlorophenoxymethyl)pyrrolidine. When the reaction is
complete, the mixture is taken up in methanol and purified by
chromatography, giving 20 mg of
7-[(R)-2-(2-chlorophenoxymethyl)pyrrolidin-1-yl]-1,2,5-thiadiazolo[3,4-b]-
pyridine (yellow crystals);
Rt: 1.830 min; [M+H].sup.+347.0;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.51 (d, 1H,
J=5.4 Hz), 7.37 (d, 1H, J=Hz); 7.22 (t, 1H, J=7.9 Hz), 7.10 (d, 1H,
J=7.9 Hz), 6.92 (d, 1H, J=7.9 Hz), 6.47 (d, 1H, J=5.4 Hz), 5.41 (m,
1H), 4.30 (dd, 1H, J=3.9 Hz, J=9.6 Hz), 4.18 (dd, 1H, J=6.0 Hz,
J=9.6 Hz), 3.90 (m 1H), 3.69 (m, 1H), 2.37 (m, 1H), 2.22 (m, 2H),
2.10 (m, 1H).
Example 12
The preparation of
N-cyclopropyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-methoxy]quinoline-2-
-carboxamide ("A14") is carried out analogously to the following
scheme
##STR00031##
12.1 1 g of commercially available 4-hydroxyquinoline-2-carboxylic
acid and 0.37 ml of commercially available cyclopropylamine are
reacted at RT for 12 h in 50 ml of DMF together with 1.7 ml of
N-methylmorpholine, 1 g of
N-(3-di-methylaminopropyl)-N'-ethylcarbodiimide hydrochloride and
0.7 g of 1-hydroxy-benzotriazole. For work-up, the batch is poured
into 50 ml of ethyl acetate and 50 ml of water. The organic phase
is extracted with saturated KHSO.sub.4 solution, dried over
magnesium sulfate and, after removal of the solvent,
chromatographed on silica gel, giving 440 mg of colourless
crystals; Rt.: 1.324 min; [M+H].sup.+229.2.
12.2 440 mg of N-cyclopropyl-4-hydroxyquinoline-2-carboxamide and
539 mg of tert-butyl
(R)-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate are reacted
with caesium carbonate in DMF and purified as described, giving 500
mg of a pale-yellow oil tert-butyl
(R)-2-(2-cyclopropylcarbamoylquinolin-4-yloxymethyl)pyrrolidine-1-carboxy-
late; Rt.: 2.274 min; [M+H].sup.+412.2.
12.3 500 mg of tert-butyl
(R)-2-(2-cyclopropylcarbamoylquinolin-4-yloxy-methyl)pyrrolidine-1-carbox-
ylate are reacted with trifluoroacetic acid in dichloromethane and
worked up, giving 80 mg of a brown oil
N-cyclopropyl-4-((R)-1-pyrrolidin-2-ylmethoxy)quinoline-2-carboxamide,
which is reacted further directly without further purification.
12.4 77 mg of 6-Cl-purine and 70 mg of
N-cyclopropyl-4-((R)-1-pyrrolidin-2-ylmethoxy)quinoline-2-carboxamide
are reacted in 1-butanol and diisopropyl-ethylamine as described.
Conventional work-up gives 25 mg of
N-cyclopropyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]quinoline-2--
carboxamide hydrochloride ("A14"); Rt.:1.919 min; [M+H].sup.+458.2;
m.p. 80-82.degree. C.
Example 13
The preparation of
2-[1-(1H-imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolid-
in-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one ("A15") and
2-(1H-imidazol-4-ylmethyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy-
]-3,4-dihydro-2H-naphthalen-1-one ("A15.1") is carried out
analogously to the following scheme
##STR00032##
13.1 3.75 g of commercially available
5-hydroxy-3,4-dihydro-2H-naphthalen-1-one are reacted with 10 g of
test-butyl (R)-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate
as described in DMF with caesium carbonate. 6.5 g of tert-butyl
(R)-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxymethyl)pyrrolidine-1-car-
boxylate are isolated; Rt.: 2.472 min; [M+H].sup.+346.2 (is only
detected in traces, the peaks of the decomposition products having
[M+H].sup.+=290.2 and 246.2 are particularly pronounced).
13.2 6.5 g of tert-butyl
(R)-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy-methyl)pyrrolidine-1-ca-
rboxylate are reacted with trifluoroacetic acid in dichloroethane
and worked up as described, giving 4.1 g of
5-((R)-1-pyrrolidin-2-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one;
Rt.: 1.325 min; [M-1-H].sup.+246.2.
13.3 5.2 g of 6-Cl-purine and 4.1 g of
5-((R)-1-pyrrolidin-2-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one
are reacted as described in 1-butanol in the microwave and
correspondingly worked up, and, after purification by
chromatography, 4.7 g of
5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-
-1-one are isolated; m.p. 205-206'; Rt.: 1.593 min;
[M+H].sup.+364.2;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s,
1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.45 (d, 1H, J=7.4 Hz), 7.30 (m,
1H), 7.26 (m, 1H), 5.38 (m, 1H), 4.80 (m, 1H), 4.37 (dd, 1H, J=3.1
Hz, J=9.4 Hz), 4.13 (dd, 1H, J=7.3 Hz, J=8.5 Hz), 3.78 (m, 1H),
2.82 (m, 2H), 2.56 (dd, 2H, J=5.5 Hz, J=7.8 Hz), 2.17 (m, 3H), 2.02
(m, 3H).
13.4 500 mg of
5-[(R)-1-(7H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-
-1-one and 520 mg of 3H-imidazole-4-carbaldehyde are heated under
reflux for 3 h with 270 mg of sodium hydroxide in 10 ml of water
and 3 ml of ethanol. After cooling, the pH is adjusted to 3 using
conc. aqueous HCl, and the mixture is stirred for 30 minutes. After
removal of the alcohol in vacuo, the mixture is neutralised using
aqueous NaOH and evaporated to dryness. The residue is
chromatographed on silica gel, giving 180 mg of colourless crystals
2-[1-(1H-imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolid-
in-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one ("A15"); m.p.
195-196.5.degree.; Rt.: 1.403 min; [M+H].sup.+442.2;
.sup.1H-NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.00 (br. s,
1H), 12.54 (br. s, 1H), 8:25 (s, 1H), 8.13 (s, 1H), 7.66 (s, 1H),
7.84 (s, 1H), 7.54 (m, 2H), 7.31 (m, 2H), 5.38 (br. m, 1H), 4.83
(br. m, 1H), 4.39 (dd, 1H J=2.7 Hz, J=9.2 Hz), 4.15 (t, 1H, J=8.1
Hz), 3.79 (br. m, 1H), 3.46 (m, 2H), 2.88 (m, 2H), 2.18 (m, 2H),
2.04 (m , 2H).
13.5 100 mg of
2-[1-(1H-imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolid-
in-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one are heated at
80.degree. C. for 30 min. together with 50 mg of zinc powder in 10
ml of conc. acetic acid and 5 ml of water. During this, the colour
changes from greenish to yellowish. The batch is adjusted to pH 7
using conc. NaOH solution and extracted to exhaustion with ethyl
acetate. The organic phase is dried over magnesium sulfate and
freed from solvent in vacuo, giving 50 mg of
2-(1H-imidazol-4-yl-methyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethox-
y]-3,4-dihydro-2H-naphthalen-1-one ("A15.1") as colourless oil.
Rt.: 1.405 min; [M+H].sup.+444.2.
The following compounds are obtained analogously to Examples
1-13
TABLE-US-00002 Compound HPLC-MS; No. Structure and/or name M.p.
[.degree. C.] rt; [M + H.sup.+]* "A15" ##STR00033##
6-[(R)-2-(2-Chlorophenoxymethyl)pyrrolidin-1-
yl]-8-methyl-9H-purine 89-91 1.711 min [344.0] .sup.1H NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] 12.70 (br. s, 1H), 8.16 (s, 1H),
7.41 (dd, 1H, J = 1.6 Hz, J = 7.6 Hz), 7.33 (m, 1H), 7.27 (dt, 1H,
J = 1.3 Hz, J = 7.2 Hz), 5.27 (m, 1H), 4.77 (m, 1H), 4.38 (m, 1H),
4.17 (dd. 1H, J = 7.1 Hz, J = 9.0 Hz), 2.44 (s, 3H), 2.26 (m, 1H),
2.11 (m, 2H), 1.99 (m, 1H) "A17" ##STR00034##
6-[(R)-2-(2-Chlorophenoxymethyl)pyrrolidin-1- yl]-8-ethyl-9H-purine
HCl 178-179 1.771 min [358.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.70 (br. s, 1H), 8.47 (s, 1H), 7.34 (d, 1H, J = 7.8
Hz), 7.29 (t, 1H, J = 7.4 Hz), 7.19 (d, 1H, J = 8.1 Hz), 6.95 (dt,
1H, J = 1.1 Hz, J = 7.8 Hz), 5.48 (m, 1H), 4.92 (m, 1H), 4.30 (m,
2H), 3.44 (m, 2H), 2.89 (m, 2H), 2.35 (m, 1H) 2.19 (m, 1H), 2.09
(s, 2H), 1.29 (t, 3H, J = 6.9 Hz) "A18" ##STR00035##
8-Bromo-6-[(R)-2-(naphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine 2.025 min [424.0; 426.0] "A19"
##STR00036## "A20" ##STR00037## "A21" ##STR00038## 258-259 .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s, 1H), 8.26
(s, 1H), 8.12 (s, 1H), 7.19 (q, 1H, J = 8.0 Hz), 7.05 (m, 1H), 6.82
(d, 1H, J = 6.5 Hz), 6.38 (dt, 1H, J = 2.0 Hz, J = 8.2 Hz), 5.31
(m, 1H), 4.65 (m, 1H), 4.21 (m, 1H), 4.00 (m, 1H), 3.84 (m, 1H),
3.06 (s, 3H), 2.17 (m, 1H), 2.00 (m, 1H), 1.91 (m, 2H) "A22"
##STR00039## .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 9.02
(dd, 1H, J = 1.2 Hz, J = 9.3 Hz), 8.93 (dd, 1H, J = 1.2 Hz, J = 8.6
Hz), 8.91 Hz (s, 1H), 7.75 (dd, 1H, J = 4.5 Hz, J = 8.5 Hz), 7.35
(dd, 1H, J = 1.2 Hz, J = 7.9 Hz), 7.24 (m, 1H), 7.12 (m, 1H), 6.90
(dt, 1H, J = 1.4 Hz, J = 7.8 Hz), 5.20 (m 1H), 4.41 (m, 3H), 4.21
(m, 1H), 2.47 (m, 1H), 2.23 (m, 2H), 2.10 (1H) "A23" ##STR00040##
4-[(R)-2-(Naphthalen-1-yloxymethyl)pyrrolidin-1-
yl]pyrido[2,3-d]pyrimidine .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 8.96 (dd, 1H, J = 1.4 Hz, J = 4.1 Hz), 8.70 (dd, 1H,
J = 1.4 Hz, J = 8.4 Hz), 8.66 (s, 1H), 8.14 (m, 1H), 7.84 (m, 1H),
7.49 (m, 4H), 7.37 (m, 1H), 7.05 (d, 1H, J = 7.6 Hz), 5.14 (m, 1H),
4.56 (dd, 1H, J = 3.3 Hz, J = 9.6 Hz), 4.37 (dd, 1H, J = 6.5 Hz, J
= 9.6 Hz), 4.24 (m, 1H), 4.02 (m, 1H), 2.25 (m, 3H), 2.01 (m, 1H)
"A24" ##STR00041## 4-[(R)-2-(2-Fluorophenoxymethyl)pyrrolidin-1-
yl]pyrrolo[2,3-d]pyrimidin-7-ylamine 1.621 min [328.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.38 (s, 1H), 7.95 (s, 2H),
7.36 (br. s, 1H), 7.19 (m, 2H), 7.11 (m, 1H) 6.94 (m, 1H), 6.76
(br. s, 1H), 4.91 (m, 1H), 4.27 (m, 1H), 4.21 (m, 1H), 4.03 (m,
1H), 3.83 (m, 1H), 2.14 (m, 4H) "A25" ##STR00042##
6-[(R)-2-(Naphthalen-1-yloxymethyl)pyrrolidin- 1-yl]purin-9-ylamine
3.95** min "A26" ##STR00043##
6-[(2R,4R)-4-Fluoro-2-(naphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 166-169 1.983 min [364.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.08 (br. s,
1H), 8.31 (s, 1H), 8.17 (s,1H), 7.87 (m, 2H), 7.56-7.37 (m, 5H),
7.11 (m, 1H), 5.59 (d, 1H, J = 54.2 Hz), 4.85-4.73 (m, 1H), 4.10
(t, 1H, J = 9.4 Hz) "A27" ##STR00044##
6-[(2R,4R)-2-(2-Chlorophenoxymethyl)-4-fluoro-
pyrrolidin-1-yl]-9H-purine 210-212 1.876 min [348.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.08 (br. s, 1H), 8.31 (s,
1H), 8.19 (s, 1H), 7.45 (dd, 1H, J = 1.5 Hz, J = 7.9 Hz), 7.38 (m,
1H), 7.30 (m, 1H), 6.97 (dt, 1H, J = 1.4 Hz, J = 7.5 Hz), 5.55 (d,
1H, J = 53.8 Hz), 4.71 (m, 1H), 3.93 (t, 1H, J = 9.5 Hz), 3.35 (m,
5H) "A28" ##STR00045## 6-[(2R,4S)-4-Fluoro-2-(naphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 168-172 1.949 min [364.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.26 (s, 1H),
8.16 (s, 1H), 8.09 (br. s,1H), 7.84 (dd, 1H, J = 2.0 Hz, J = 6.4
Hz), 7.50 (m, 5H), 7.36 (t, 1H, J = 8.0 Hz), 5.63 (d, 1H, J = 54.0
Hz), 4.50-4.55 (m, 7H) "A29" ##STR00046##
6-[(R)-2-(2-Chlorophenoxymethyl)-4,4-difluoro-
pyrrolidin-1-yl]-9H-purine "A30" ##STR00047##
(3R,5R)-5-(Naphthalen-1-yloxymethyl)-1-(9H-
purin-6-yl)pyrrolidin-3-ol 132-134 1.640 min [362.2] "A31"
##STR00048## 6-[(R)-2,2-Difluoro-5-(naphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine "A32" ##STR00049##
6-(3,5-Difluorophenyl)-2-[1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethyl]-2H-pyridazin-3-one 148-150 2.85 min**
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.83 (br. s,
1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.95 (d, 1H, J = 9.8 Hz), 7.35 (s,
1H), 7.24 (m, 2H), 7.01 (d, 1H, J = 9.8 Hz), 5.61 (m, 1H), 5.12 (m,
1H), 4.59 (m, 1H), 4.34 (dd, 1H, J = 6.3 Hz, J = 12.9 Hz), 4.14 (m,
1H), 1.98 (m, 4H) "A33" ##STR00050##
N-[6-(3-{2-[1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-5-trifluoromethylphenyl}ureido-
methyl)-1H-benzimidazol-2-yl]acetamide 190-192 1.733 min [609.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s,
1H), 11.95 (d, 1H, J = 9.8 Hz), 11.46 (m, 1H), 8.57 (m, 1H), 8.25
(m, 1H), 8.11 (m, 1H), 7.59 (br. s, 1H), 7.56 (m, 1H), 7.38 (m,
1H), 7.23 (m, 1H), 7.07 (m, 1H), 5.36 (m, 1H), 4.77 (m, 1H), 4.52
(dd, 1H, J = 3.6 Hz, J = 9.4 Hz), 4.38 (m, 2H), 3.99 (t, 1H, 9.8
Hz), 3.74 (m, 1H), 2.15 (s, 3H), 2.04 (m, 4) "A34" ##STR00051##
N-Methyl-4-[4-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-5-trifluoromethyl-phenyl}
ureidomethyl)phenoxy]pyridine-2-carboxamide 180-183 1.975 min
[662.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.99
(br. s, 1H), 8.74 (br. q, 1H, J = 4.9 Hz), 8.55 (d, 1H, J = 2.0
Hz), 8.51 (d, 1H, J = 5.7 Hz), 8.27 (br. s, 1H), 8.14 (s, 2H), 7.69
(br. s, 1H), 7.48 (d, 3H, J = 8.4 Hz), 7.38 (d, 1H, J = 2.6 Hz),
7.26 (br. s, 1H), 7.23 (d, 2H, J = 8.4 Hz), 7.17 (dd, 1H, J = 2.5
Hz, J = 5.5 Hz), 5.36 (m, 1H), 4.81 (m, 1H), 4.57 (dd, 1H, J = 3.5
Hz, J = 9.6 Hz), 4.39 (m, 2H), 4.01 (t, 1H, J = 9.7 Hz), 3.73 (m,
1H), 2.78 (d, 3H, J = 4.9 Hz), 2.07 (m, 4H) "A35" ##STR00052##
N-Methyl-4-[4-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-5-trifluoromethylphenyl}ureido)-
phenoxy]pyridine-2-carboxamide "A36" ##STR00053##
N-Methyl-4-[3-(3-{2-[1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]-5-trifluoromethyl-
phenyl}ureido)phenoxy]pyridine-2-carboxamide "A37" ##STR00054##
237-238 2.069 min [386.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.98 (br. s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 8.08
(d, 1H, J = 7.6 Hz), 7.80 (br. s, 1H), 7.65 (d, 1H, J = 8.4 Hz),
7.59 (d, 1H, J = 8.9 Hz), 7.50 (dd, 1H, J = 1.2 Hz, J = 7.3 Hz),
7.36 (t, 1H, J = 7.3 Hz), 7.17 (br. dd, J = 1.4 Hz, J = 8.8 Hz),
5.36 (br. m, 1H), 4.82 (br. m, 1H), 4.46 (dd, 1H, J = 3.1 Hz, J =
9.1 Hz), 4.12 (t, 1H, J = 8.6 Hz), 3.80 (br. m, 1H), 2.20 (br. m,
1H), 2.15 (br. m, 2H), 2.04 (br. m, 1H) "A38" ##STR00055##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]- 9H-carbazole
165-167 1.862 min [385.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.99 (br. s, 1H), 11.26 (br. s, 1H), 8.26 (s, 1H),
8.14 (br. m, 1H), 8.12 (s, 1H), 7.45 (d, 1H, J = 8.2 Hz), 7.34 (dd,
1H, J = 0.8 Hz, J = 7.1 Hz), 7.26 (br. t, 1H, J = 8.0 hz), 7.14
(br. t, 1H, J = 7.4 Hz), 7.06 (d, 1H, J = 8.0 Hz), 6.79 (br. m,
1H), 5.52 (br. m, 1H), 4.97 (br. m, 1H), 4.61 (dd, 1H, J = 3.6 Hz,
J = 8.9 Hz), 4.22 (m, 1H), 3.83 (br. m, 1H), 2.24 (m, 3H), 2.06 (m,
1H) "A39" ##STR00056## Ethyl
1-butyl-2-methyl-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1H-indole-3-carboxylate 110-111 2.107 min
[477.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.94
(br. s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 7.40 (d, 1H,
J = 8.7 Hz), 6.88 (br. d, 1H, J = 8.7 Hz), 5.28 (br. m, 1H), 4.78
(br. m, 1H), 4.34 (dd, 1H, J = 3.0 Hz, J = 8.9 Hz), 4.24 (q, 2H, J
= 7.0 Hz), 4.14 (t, 2H, J = 7.0 Hz), 4.06 (br. t, 1H, J = 8.1 Hz),
3.80 (br. m, 1H), 2.68 (s, 3H), 2.19 (m, 1H), 2.12 (m, 2H), 2.01
(1H), 1.62 (quint, 2H, J = 7.3 Hz), 1.29 (m, 7H), 0.88 (t, 3H, J =
7.0 Hz) "A40" ##STR00057##
6-[(R)-2-(1H-lndol-4-yloxymethyl)pyrrolidin-1-yl]- 9H-purine
214-216 1.554 min [335.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.94 (br. s, 1H), 11.03 (br. s, 1H), 8.23 (s, 1H),
8.09 (s, 1H), 7.19 (m, 1H), 6.95 (m, 2H), 5.53 (br. m, 1H), 6.38
(m, 1H), 5.36 (br. m, 1H), 4.84 (br. m, 1H), 4.39 (dd, 1H, J = 3.2
Hz, J = 9.0 Hz), 4.19 (dd, 1H, J = 7.0 Hz, J = 9.0 Hz), 4.04 (br.
m, 1H), 2.25 (m, 1H), 2.15 (m, 2H), 2.04 (m, 1H). "A41"
##STR00058## 1-{7-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]benzofuran-2-yl}ethanone 210-212 1.599 min [378.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s, 1H), 8.24
(s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.36 (d, 1H, J = 8.0 Hz), 7.26
(br. m, 2H), 5.38 (br. m, 1H), 4.84 (br. m, 1H), 4.53 (dd, 1H, J =
3.1 Hz, J = 9.2 Hz), 4.27 (dd, 1H, J = 8.2 Hz, J = 9.2 Hz), 3.79
(br. m, 1H), 2.56 (s, 3H), 2.24 (m, 1H), 2.16 (m, 1H), 2.04 (m, 2H)
"A42" ##STR00059## 5-Piperidin-1-ylmethyl-8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline formate 1.226 min [444.2] "A43"
##STR00060## 8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline 222-223 1.229 min [347.2] "A44" ##STR00061##
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl- methoxy]isoquinoline
154-155 1.390 min [347.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 13.04 (br. s, 1H) 9.26 (s, 1H), 8.51 (d, 1H, J = 5.8
Hz), 8.25 (s, 1H), 8.13 (s, 1H), 7.91 (br. s, 1H), 7.65 (d, 1H, J =
8.2 Hz), 7.56 (t, 1H, J = 7.9 Hz), 7.36 (br. s, 1H), 5.34 (br. m,
1H), 4.93 (br. m, 1H), 4.54 (dd, 1H, J = 3.2 Hz, J = 9.2 Hz), 4.29
(br. t, 1H, J = 8.2 Hz), 3.84 (br. m, 1H), 2.23 (br. m, 3H), 2.07
(br. m, 1H). "A45" ##STR00062##
7-Benzyloxy-6-methoxy-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinazoline 161-163 1.951** "A46"
##STR00063## 4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]quinazoline 1.456 min [348.2] "A47" ##STR00064##
2-{2-[2-({4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}-amino)ethoxy]ethoxy}ethylamine 1.403
min [506.2] "A48" ##STR00065##
N-Methyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide formate 1.555 min [404.2] "A49"
##STR00066## 2-Methyl-8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline 130-131 1.214** "A50" ##STR00067##
N-Ethyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide formate 1.626 min [418.2]
.sup.1HNMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.99 (br. s, 1H),
8.85 (t, 1H, J = 5.9 Hz), 8.34 (br. s, 2H), 8.14 (br. m, 1H), 8.06
(d, 1H, J = 8.8 Hz), 7.84 (ddd, 1H, J = 1.1 Hz, J = 7.0 Hz, J = 8.3
Hz), 7.66 (t, 1H, J = 7.6 Hz), 5.44 (br. m, 1H), 4.88 (br. m, 1H),
4.74 (dd, 1H, J = 3.3 Hz, J =
9.6 Hz), 4.46 (br. t, 1H), 3.98 (br. m, 1H), 3.38 (q, 2H, J = 6.7
Hz), 2.25 (br. m, 2H), 2.19 (br. m, 1H), 2.07 (br. m, 1H), 1.17 (t,
3H, J = 7.2 Hz) "A51" ##STR00068##
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
3(4-dihydro-2H-naphthalen-1-one 205-206 1.593 min [364.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s, 1H), 8.23
(s, 1H), 8.11 (s, 1H), 7.45 (d, 1H, J = 7.4 Hz), 7.30 (m, 1H), 7.26
(m, 1H), 5.38 (m, 1H), 4.80 (m, 1H), 4.37 (dd, 1H, J = 3.1 Hz, J =
9.4 Hz), 4.13 (dd, 1H, J = 7.3 Hz, J = 8.5 Hz), 3.78 (m, 1H), 2.82
(m, 2H), 2.56 (dd, 2H, J = 5.5 Hz, J = 7.8 Hz), 2.17 (m, 3H), 2.02
(m, 3H) "A52" ##STR00069##
2-Hydroxymethylene-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one "A53"
##STR00070## [1-Oxo-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-naphthalen-(2Z)-ylidene]acetic acid 256-257
1.582 min [420.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
8.23 (s, 1H), 8.11 (s, 1H), 7.50 (d, 1H), 7.28 (m, 2H), 6.70 (s,
1H), 5.33 (br. m, 1H), 4.85 (br. m, 1H), 4.37 (dd, 1H, J = 3.5 Hz,
J = 9.3 Hz), 4.12 (t, 1H, J = 8.1 Hz), 3.84 (br. m, 1H), 3.00 (m,
2H), 2.77 (m, 2H), 2.16 (m, 3H), 2.02 (m, 1H) "A54" ##STR00071##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
3,4-dihydro-1H-naphthalen-2-one "A55" ##STR00072##
6-[(R)-2-(5,6,7,8-Tetrahydronaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 138-140 1.902 min [350.2]
.sup.1HNMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.27 (s, 1H), 8.17
(s, 1H), 6.98 (t, 1H, J = 7.8 Hz), 6.75 (m, 1H), 6.62 (d, 1H, J =
7.8 Hz), 5.36 (m, 1H), 4.79 (m, 1H), 4.25 (dd, 1H, J = 3.5 Hz, J =
9.3 Hz), 4.07 (dd, 1H, J = 6.9 Hz, J = 9.3 Hz), 3.79 (m, 1H), 2.65
(m, 4H), 2.20-2.00 (m, 4H), 1.68 (m, 4H) "A56" ##STR00073##
4-Morpholin-4-ylmethyl-8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline 112-114 1.090** "A57" ##STR00074##
1 -Chloro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline 102-104 1.761 min [381.2] .sup.1H NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] 12.99 (br. s, 1H), 8.73 (s, 1H),
8.65 (s, 1H), 8.25(s, 1H), 8.22 (m, 1H), 8.12 (m, 1H), 8.09 (m,
1H), 7.92 (m, 1H), 4.62 (dd, 1H, J = 3.5 Hz, J = 9.2 Hz), 4.45 (dd,
1H, J = 7.9 Hz, J = 8.8 Hz), 4.38 (dd, 1H, J = 7.9 Hz, J = 8.8 Hz),
4.16 (dd, J = 3.5 Hz, J = 8.8 Hz), 3.88 (m, 1H), 2.23 (m, 4H) "A58"
##STR00075## 6-{(R)-2-[5-(2-Methoxyethoxy)naphthalen-1-yl-
oxymethyl]pyrrolidin-1-yl}-9H-purine 206-207 1.589 min [313.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.95 (br. s,
1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.71 (m, 2H), 7.38 (m, 2H), 7.08
(m, 1H), 7.00 (d, 1H, J = 7.7 Hz), 5.43 (m, 1H), 4.92 (m, 1H), 4.50
(dd, 1H, J = 3.2 Hz, J = 9.1 Hz), 4.27 (m, 4H), 3.81(m, 2H), 3.38
(s, 3H), 2.25 (m, 3H), 2.07 (m, 1H) "A59" ##STR00076##
2-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethyl]-
2H-isoquinolin-1-one 134-136 1.615 min [347.2] .sup.1H NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] "A60" ##STR00077##
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-1-yl- methyl}amine 106-108 1.331
min [488.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.93
(br. s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.14 (d, 1H, J = 8.4 Hz),
8.10 (s, 1H), 7.57 (m, 1H), 7.52 (m, 1H), 7.37 (d, 1H, J = 7.6 Hz),
7.00 (m 1H), 5.47 (m, 1H), 4.90 (m, 1H), 4.50 (dd, 1H, J = 3.4 Hz,
J = 9.2 Hz), 4.25 (m, 1H), 4.12 (m, 2H), 3.51 (m, 4H), 3.31 (m,
4H), 2.73, (m, 2H), 2.42 (m, 1H), 2.31 (m, 4H), 2.23 (m 1H), 2.07
(m, 1H) "A61" ##STR00078##
6-[(R)-2-(2-Piperidin-1-ylmethylnaphthalen-1-
yloxymethyl)pyrroiidin-1-yl]-9H-purine 1.544 min [443.2] "A62"
##STR00079## 6-[(R)-2-(Biphenyl-2-yloxymethyl)pyrrolidin-1-
yl]-9H-purine 154-156 1.849 min [372.2] .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 12.95 (br. S, 1H), 8.22 (s, 1H), 8.10
(s, 1H), 7.47 (m, 2H), 7.41 (t, 2H, J = 7.6 Hz), 7.34-7.26 (m, 4H),
7.01 (t, 2H, J = 7.6 Hz), 5.20 (m, 1H), 4.65 (m, 1H), 4.31 (m, 1H),
4.17 (m, 1H), 3.61 (m, 1H), 2.03-1.82 (m, 4H) "A63" ##STR00080##
6-[(R)-2-(Biphenyl-3-yloxymethyl)pyrrolidin-1- yl]-9H-purine
152-153 1.930 min [372.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.96 (br. S, 1H), 8.22 (s, 1H), 8.09 (s,1H), 7.63
(d, 2H, J = 7.7 Hz), 7.44 (t, 2H, J = 7.7 Hz), 7.35 (t, 2H, J = 7.7
Hz), 7.21 (d, 1H, J = 7.7 Hz), 7.00 (d, 1H = J = 7.7 Hz), 5.30 (m,
1H), 4.79 (m, 1H), 4.43 (dd, 1H, J = 3.3 Hz, J = 9.6 Hz), 4.11 (dd,
1H, J = 8.6 Hz, J = 9.6 Hz), 3.78 (m, 1H), 2.20-2.00 (m, 4H) "A64"
##STR00081## 6-[(R)-2-(Biphenyl-4-yloxymethyl)pyrrolidin-1-yl]-
9H-purine 255-256 1.970 min [372.2] .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 8.24 (s, 1H), 8.10 (s, 1H), 7.59 (m,
4H), 7.42 (m, 2H), 7.29 (m, 1H), 7.11 (d, 2H, J = 8.5 Hz), 5.00 (m,
1H), 4.39 (dd, 1H, J = 3.0 Hz, J = 9.1 Hz), 4.06 (dd, 1H, J =8.2
Hz, J = 9.1 Hz), 3.90 (m, 1H), 3.34 (m, 1H), 2.20 - 2.00 (m, 4H)
"A65" ##STR00082## Methyl
3-{5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]pyrimidin-2-yl}benzoate 210-211 1.764 min [432.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.99 (br. s, 1H), 8.90
(s, 1H), 8.75 (s, 2H), 8.54 (d, 1H, J = 7.7 Hz), 8.25 (s, 1H), 8.12
(s, 1H), 8.04 (d, 1H, J = 7.7 Hz), 7.65 (t, 1H, J = 7.7 Hz), 5.33
(br. m, 1H), 4.80 (br. m, 1H), 4.56 (d, 1H, J = 7.7 Hz), 4.27 (t,
1H, J = 8.8 Hz), 4.06 (br. m, 1H), 3.90 (s, 3H), 2.15 (br. m, 3H),
2.03 (br. m, 1H) "A66" ##STR00083##
N-(2-Morpholin-4-ylethyl)-3-{5-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]pyrimidin-2-yl}-benzamide 144-145 1.410
min [530.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.75
(s, 3H), 8.54 (t, 1H, J = 5.5 Hz), 8.41 (d, 1H, J = 7.8 Hz), 8.22
(s, 1H), 8.02 (s, 1H), 7.90 (d, 1H, J = 7.8 Hz), 7.57 (t, 1H, J =
7.8 Hz), 5.04 (br. m, 1H), 4.57 (dd, 1H, J = 3.3 Hz, J = 9.1 Hz),
4.26 (t, 1H, J = 8.7 Hz), 3.90 (br. m, 2H), 3.58 (m, 4H), 3.41 (m,
2), 3.29 (m, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.43 (m, 4H). "A67"
##STR00084## N-Methyl-2-[1-oxo-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-
naphthalen-(2Z)-ylidene]acetamide 138-140 1.559 min [433.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s, 1H), 8.42
(m, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.55 (d, 1H, J = 8.24 Hz),
7.35 (m, 2H), 6.79 (s, 1H), 5.36 (m, 1H), 4.83 (m, 1H), 4.40 (dd,
1H, J = 3.1 Hz, J = 9.3 Hz), 4.15 (t, 1H, J = 8.1 Hz), 3.81 (m,
1H), 3.38 (m, 1H), 2.87 (m, 1H), 2.70 (d, 3H, 4.7 Hz), 2.18 (m,
3H), 2.04 (m, 1H). "A68" ##STR00085##
N-(2-Hydroxypropyl)-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide hydrochloride
125-127 1.546 min [448.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] "A69" ##STR00086##
N-Cyclopentyl-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide 1.724 min [430.2]
"A70" ##STR00087## N-Butyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide 1.920 min [446.2] "A71"
##STR00088## N-Propyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide 1.793 min [432.2] "A72"
##STR00089## 6-[(R)-2-(2,2-Dimethyl-2,3-dihydrobenzofuran-
7-yloxymethyl)pyrro!idin-1-yl]-9H-purine 184-185 1.873 min [366.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s,
1H), 8.23 (s, 1H), 8.11 (s, 1H), 6.89 (br. s, 1H), 6.75 (d, 1H, J =
7.2 Hz), 6.68 (t, 1H, J = 7.6 Hz), 5.24 (br. m, 1H), 4.70 (br. m,
1H), 4.30 (dd, 1H, J = 2.7 Hz, J = 8.9 Hz), 3.98 (t, 1H, J = 8.7
Hz), 3.71 (br. m 1H), 3.33 (s, 2H), 2.14-2.00 (m, 4H), 1.40 s, 3H),
1.39 (s, 3H). "A73" ##STR00090##
6-[(R)-2-(Benzoxazol-4-yloxymethyl)pyrrolidin- 1-yl]-9H-purine
215-216 1.597 min [337.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.95 (br. s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.11
(s, 1H), 7.31 (m, 2H), 7.06 (br. m, 1H), 5.29-4.81 (br. m, 1H),
4.57 (dd, 1H, J = 1.7 Hz, J = 8.7 Hz), 4.35 (dd, 1H, J = 7.7 Hz, J
= 9.3 Hz), 3.76 (m, 2H), 2.26 (m, 1H), 2.14 (m, 2H), 2.02 (m, 1H).
"A74" ##STR00091## Ethyl
(E)-3-{2-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]phenyl}acrylate 104.5-106 1.924 min [394.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s, 1H), 8.23 (s,
1H), 8.11 (s, 1H), 7.95 (d, 1H, J = 16.0 Hz), 7.71 (dd, 1H, J = 1.4
Hz, = 7.7 Hz), 7.37 (t, 1H, J = 7.6 Hz), 7.20 (br. s, 1H), 6.97 (t,
1H, J = 7.5 Hz), 6.59 (d, 1H, J = 16.0 Hz), 5.33 (br. m, 1H), 4.79
(br. m, 1H), 4.42 (dd, 1H, J = 1.8 Hz, J = 8.9 Hz), 4.23 (m, 1H),
4.20 (q, 2H, J = 7.1 Hz), 3.79 (br. m, 1H), 2.18 (m, 3H), 2.04 (m,
1H), 1.28 (t, 3H, J =7.1 Hz). "A75" ##STR00092##
2,2,2-Trifluoro-1-{2-methyl-4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]indol-1-yl}ethanone 142-144 1.869 min
[445.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96
(br. s, 1H), 12.31 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.13 (m,
1H), 7.02 (m, 2H), 5.33 (br. m, 1H), 4.79 (br. m, 1H), 4.48 (dd,
1H, J = 3.3 Hz, J = 9.3 Hz), 4.26 (br. m, 1H), 3.95 (m, 1H), 2.49
(s, 3H), 2.14-2.10 (m, 4H). "A76" ##STR00093##
(E)-3-{2-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]phenyl}acrylic acid 144-146 1.599 min [366.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.15 (br. s, 1H), 12.34 (br.
s, 1H),8.29 (s, 1H), 8.19 (s, 1H), 7.87 (d, 1H, J = 16.1 Hz), 7.68
(dd, 1H J = 1.3 Hz, J = 7.6 Hz), 7.37 (t, 1H, J = 7.4 Hz), 7.20
(br. s, 1H), 6.97 (t, 1H, J = 7.5 Hz), 6.52 (d, 1H, J = 16.1 Hz),
5.37-4.81 (br. m, 1H), 4.42 (dd, 1H, J = 2.6 Hz, J = 9.1 Hz), 4.24
(m, 1H), 4.17 (t, 1H, J = 8.5 Hz), 3.80 (br. m, 1H), 2.18 (m, 3H),
2.05 (m, 1H). "A77" ##STR00094##
6-{(R)-2-[2-(4-Fluorophenyl)pyrimidin-5-yl-
oxymethyl]pyrrolidin-1-yl}-9H-purine 194-196 1.815 min [392.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.00 (br. s,
1H), 8.71 (s, 2H), 8.33 (d, 1H, J = 5.7 Hz), 8.31 d, 1H, J = 5.7
Hz), 8.24 (s, 1H), 8.13 (s, 1H), 7.31 (t, 2H, J = 8.8 Hz), 5.29
(br. m, 1H), 4.77 (br. m, 1H), 4.53 (dd, 1H, J = 2.6 Hz, J = 9.4
Hz), 4.24 (t, 1H, J = 8.6 Hz), 3.76 (m, 1H), 2.13 (m, 3H), 2.01 (m,
1H). "A78" ##STR00095## (E)-N-Methyl-3-{2-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]phenyl}acrylamide 112-114 1.668 min [379.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.95 (br. s,
1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.02 (q, 1H, J = 4.6 Hz), 7.72 (d,
1H, J = 15.9 Hz), 7.50 (dd, 1H, J = 1.3 Hz, J = 7.6 Hz), 7.31 (t,
1H, J = 7.2 Hz), 7.19 (br. m, 1H), 6.96 (t, 1H, J = 7.5 Hz), 6.61
(d, 1H, J = 15.9 Hz), 5.33-4.81 (m, 1H), 4.42 (dd, 1H, J = 2.7 Hz,
J = 9.1 Hz), 4.10 (t, 1H, J = 8.6 Hz), 3.80 (m, 2H), 2.72 (d, 3H, J
= 4.8 Hz), 2.16 (m, 3H), 2.02 (m, 1H). "A79" ##STR00096##
(E)-N-(3-Hydroxypropyl)-3-{2-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]phenyl}acrylamide 114-116 1.633 min
[423.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96
(br. s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 8.06 (t, 1H, J = 5.55 Hz),
7.73 (d, 1H, J = 15.8 Hz), 7.51 (dd, 1H, J = 1.3 Hz, J = 7.7 Hz),
7.31 (t, 1H, J = 6.8 Hz), 7.19 (br. s, 1H), 6.96 (t, 1H, J = 7.5
Hz), 6.62 (d, 1H, J = 15.8 Hz), 5.34-4.81 (m, 1H), 4.46 (t, 1H, J =
4.9 Hz), 4.42 (dd, 1H, J = 2.4 Hz, J = 9.0 Hz), 4.26 (m, 1H), 4 11
(t, 1H, J = 8.5 Hz), 3.80 (m, 1H), 3.45 (m, 2H), 3.24 (m, 2H), 2.16
(m, 3H), 2.02 (m, 1H), 1.63 (m, 2H). "A80" ##STR00097##
N-Cyclobutyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]quinoline-2-carboxamide 160-161 .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 12.99 (br. s, 1H), 8.95 (d, 1H), J =
8.5 Hz), 8.39 (br. m, 1H), 8.14 (br. m, 2H), 8.09 (d, 1H, J = 8.4
Hz), 7.84 (ddd, 1H, J = 1.3 Hz, J = 6.9 Hz, J = 8.3 Hz), 7.66 (m,
1H), 5.46-4.91 (m, 1H), 4.73 (dd, 1H, J = 3.4 Hz, J = 9.8 Hz),
4.52-4.42 (m,
2H), 4.07 (m, 1H), 3.83 (m, 1H), 3.45 (m,1H), 2.22 (m, 7H), 2.07
(m, 1H), 1.70 (m, 2H). "A81" ##STR00098##
N-Pentyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxamide 150-152 .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 13.00 (br. s, 1H), 8.84 (t, 1H, J = 6.1
Hz), 8.39 (br. m, 1H), 8.14 (br. s, 2H), 8.06 (d, 1H, J = 8.3 Hz),
7.84 (ddd, 1H, J = 1.3 Hz, J = 6.9 Hz, J = 8.3 Hz), 7.66 (m, 1H),
5.47-4.90 (m, 1H), 4.74 (dd, 1H, J = 3.3 Hz, J = 9.6 Hz), 4.46 (m,
1H), 4.33 (m, 1H), 4.09 (m, 1H), 3.89 (m, 1H), 3.33 (m, 1H), 2.25
(m, 3H), 2.07 (m, 1H), 1.57 (m, 2H), 1.31 (m, 4H), 0.88 (m, 3H).
"A82" ##STR00099## 2-[1-(4-Chloro-2-methyl-2H-pyrazol-3-yl)meth-
(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one 150.5-152 1.865 min
[490.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96
(br. s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.62 (d, 1H,
J = 7.7 Hz), 7.37 (m, 2H), 7.30 (s, 1H), 5.35 (m, 1H), 4.80 (m,
1H), 4.40 (dd, 1H, J = 3.0 Hz, J = 9.4 Hz), 4.16 (t, 1H, J = 8.3
Hz), 3.8 (s, 3H), 2.90 (m, 2H), 2.78 (m, 2H), 2.16 (m, 3H), 2.02
(m, 2H). "A83" ##STR00100##
5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
2-[1-(1H-pyrazol-3-yl)meth-(Z)-yildene]-3,4-
dihydro-2H-naphthaien-1-one 174-176 1.658 min [442.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.29 (br. s, 1H), 12.97 (br.
s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.86 (br. s, 1H), 7.65 (br. m,
1H), 7.56 (m, 2H), 7.34 (m, 2H), 4.84 (br. m, 1H), 3.81 (br. m,
2H), 4.40 (dd, 1H, J = 2.6 Hz, J = 8.8 Hz), 4.15 (t, 1H, J = 8.0
Hz), 3.08 (br. m, 1H), 2.91 (br. m, 3H), 2.18 (m, 3H), 2.04 (m,
1H). "A84" ##STR00101##
N-(2-Hydroxyethyl)-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide >299 1.177 min
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.06 (br. s,
1H), 8.77 (t, 1H, J = 5.7 Hz), 8.41 (br. m, 1H), 8.16 (br. s, 2H),
8.06 (d, 1H, J = 8.4 Hz), 7.84 (ddd, 1H, J = 1.2 Hz, J = 7.0 Hz, J
= 8.2 Hz), 7.66 (t, 1H, J = 7.5 Hz), 5.48-4.90 (m, 1H), 4.75 (dd,
1H, J = 3.5 Hz, J = 9.7 Hz), 4.30-4.08 (m, 1H), 3.84 (m, 1H), 3.57
(t, 2H, J = 5.9 Hz), 3.44 (q, 2H, J = 5.9 Hz), 2.26-2.19 (m, 3H),
2.08 (m, 1H). "A85" ##STR00102##
N-(3-Hydroxypropyl)-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide >299 1.510 min
[448.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.08
(br. s, 1H), 8.89 (t, 1H, J = 5.9 Hz), 8.39 (br. m, 1H), 8.16 (br.
s, 2H), 8.04 (d, 1H, J = 8.4 Hz), 7.84 (ddd, 1H, J = 1.2 Hz, J =
7.0 Hz, J = 8.3 Hz), 7.66 (t, 1H, J = 7.5 Hz), 5.47-4.90 (m, 1H),
4.74 (dd, 1H, J = 3.5 Hz, J = 9.7 Hz), 4.58-4.29 (m, 1H), 4.07-3.89
(m, 1H), 3.49 (t, 2H, J = 6.2 Hz), 3.42 (q, 3H, J = 6.5 Hz),
2.26-2.20(m, 3H), 2.08 (m, 1H), 1.72 (quint., 2H, J = 6.4 Hz).
"A86" ##STR00103## 5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline 93-94 1.216 min [347.2] .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 8.89 (dd, 1H, J = 1.5 Hz, J = 4.1 Hz),
8.48 (br. d, 1H, J = 6.5 Hz), 8.24 (s, 1H), 8.10 (s, 1H), 7.64 (t,
1H, J = 8.2 Hz), 7.58 (d, 1H, J = 8.4 Hz), 7.52 (dd, 1H, J = 4.2
Hz, J = 8.4 Hz), 7.17 (br. d, J = 6.5 Hz), 5.22 (br. m, 1H), 4.54
(dd, 1H, J = 3.5 Hz, J = 9.3 Hz), 4.29 (dd, 1H, J = 7.7 Hz, J = 9.3
Hz), 4.00 (br. m, 2H), 2.23 (m, 3H), 2.06 (m, 1H). "A87"
##STR00104## 8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline 134-136 1.222 min [347.2] .sup.1H NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] 12.98 (br. s, 1H), 9.45 (br. s,
1H), 8.51 (d, 1H, J = 5.8 Hz), 8.26 (s, 1H), 8.12 (s, 1H), 7.76 (d,
1H, J = 5.8 Hz), 7.66 (t, 1H, J = 8.1 Hz), 7.49 (d, 1H, J = 8.1
Hz), 7.24 (br. s, 1H), 5.42-4.95 (m, 1H), 4.57 (dd, 1H, J = 3.3 Hz,
J = 9.2 Hz), 4.33 (t, 1H, J = 8.0 Hz), 3.87 (m, 2H), 2.25 (m, 3H),
2.08 (m, 1H). "A88" ##STR00105##
N-(3-Hydroxycyclobutylmethyl)-4-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]quinoline-2- carboxamide 116-117
1.557 min [474.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
13.00 (br. s, 1H), 8.82 (t, 1H, J = 6.0 Hz), 8.39 (br. m, 1H), 8.15
(br. s, 2H), 8.07 (d, 1H, J = 8.4 Hz), 7.85 (t, 1H, J = 7.4 Hz),
7.67 (t, 1H, J = 7.4 Hz), 5.47 (m, 1H), 4.94 (m, 1H), 4.76 (dd, 1H,
J = 3.3 Hz, J = 9.8 Hz), 4.47 (m, 1H), 3.89 (quint. 1H, J = 7.4
Hz), 3.37 (m, 3H), 2.26 (m, 4H), 2.08 (m, 1H), 1.99 (m, 2H), 1.58
(m, 2H). "A89" ##STR00106##
3-Methyl-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline 137-138 1.258 min [361.2] .sup.1H NMR (500
MHz, d.sub.6-DMSO) .delta. [ppm] 12.99 (br. s, 1H), 9.15 (s, 1H),
8.26 (s, 1H), 8.12 (s, 1H), 7.59 (d, 1H, J = 8.12 Hz), 7.46 (t, 1H,
J = ) 7.7 Hz, 7.29 (br. s, 1H), 5.53 (br. m, 1H), 4.95 (br. m, 1H),
4.50 (dd, 1H, J = 4.0 Hz, J = 9.1 Hz), 4.25 (t, 1H, J = 8.4 Hz),
3.84 (br. m, 1H), 2.61 (s, 3H), 2.21 (m, 3H), 2.07 (m,1H). "A90"
##STR00107## 7-[(R)-2-(2-Chlorophenoxymethyl)pyrrolidin-1-
yl]-3H-imidazo[4,5-b]pyridine 2.69 min** "A91" ##STR00108##
4-[(R)-2-(2-Chlorophenoxymethyl)pyrrolidin-1-
yl]-1H-pyrazolo[3,4-d]pyrimidine 2.68 min** "A92" ##STR00109##
N-(2-Morpholin-4-ylethyl)-N-{4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl-methyl}acetamide
150-151 1.44- 1 min [530.2] "A93" ##STR00110##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl- methoxy]quinoline
130-131.5 1.240 min [347.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 8.71 (d, 1H, J = 5.1 Hz), 8.27 (s, 1H), 8.13 (s, 1H),
8.11 (br. s, 1H), 7.95 (d, 1H, J = 8.4 Hz); 7.75 (ddd, 1H, J = 1.3
Hz, J = 6.9 Hz, J = 8.3 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.17 (br. s,
1H), 5.47-4.98 4.98 (br. m, 1H), 4.61 (dd, 1H, J = 3.4 Hz, J = 9.5
Hz), 4.38 (t, 1H, J = 8.3 Hz), 4.11 (m, 1H), 3.86 (m, 1H), 2.23 (m,
3H), 2.11 (m, 1H). "A94" ##STR00111##
N-(2-Morpholin-4-ylethyl)-N-{4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl-methyl}formamide
184-187 1.44- 4 min [516.3] "A95" ##STR00112##
(3-Morpholin-4-ylpropyl)-{4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl-methyl}amine 148-150
"A96" ##STR00113## (R)-2-(1H-Imidazol-4-ylmethyl)-5-[(R)-1-(9H-
purin-6-yl)pyrrolidin-ylmethoxy]-3,4-dihydro- 2H-naphthalen-1-one
"A97" ##STR00114## (S)-2-(1H-Imidazol-4-y!methyl)-5-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro- 2H-naphthalen-1-one
"A98" ##STR00115## N-(2-Piperidin-1-ylethyl)-N-{4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl- methyl]acetamide
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.23 (s, 1H),
8.18 (br. m, 1H), 8.10 (s, 1H), 8.00 (m, 1H), 7.64-7.51 (m, 2H),
7.28 (d, 1H, J = 8.0 Hz), 7.03 (m, 1H), 4.99 (s, 1H), 4.92 (s, 1H),
4.52 (dd, 1H, J = 3.3 Hz, J = 9.1 Hz), 3.20 (m, 3H), 2.24 (m, 9H),
2.12 (s, 3H), 2.06 (m 1H), 1.41 (m, 4H), 1.32 (m, 2H). "A99"
##STR00116## N-(1-Methyl-1H-pyrazol-3-ylmethyl)-N-{4-[(R)-
1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
naphthalen-1-ylmethyl}acetamide 117-119 1.466 min [511.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s. 1H), 8.25
(s, 1H), 8.19 (br. m, 1H), 8.12 (s, 1H), 8.06 (m, 1H), 7.60-7.51
(m, 4H), 7.28 (br. d, 1H, J = 7.7 Hz), 7.07 (br. m, 1H), 7.03 (br.
m 1H), 6.04 (d, 1H, J = 1.9 Hz), 5.48 (br. m, 1H), 4.87 (s, 2H),
4.53 (dd, 1H, J = 3.1 Hz, J = 9.1 Hz), 4.27 (m, 1H), 4.24 (s, 3H),
2.24 (m 3H), 2.19 (s, 3H), 2.07 (m 1H). "A100" ##STR00117##
N-(2,3-Dihydroxypropyl)-N-{4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl- methyl}acetamide
Decomposition from 145.degree. 1.652 min [491.2] "A101"
##STR00118## N-(2-Piperidin-1-ylethyl)-N-{4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]naphthalen-1-yl- methyl}formamide
Decomposition from 190.degree. 1.511 min [514.2] "A102"
##STR00119## N-(1-Methyl-1H-pyrazol-3-ylmethyl)-N-{4-[(R)-
1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
naphthalen-1-ylmethyl}formamide 206-207 1.568 min [497.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.00 (br. s, 1H), 8.29
(s, 1H), 8.24 (s, 1H), 8.20 (br. s, 1H), 8.11 (s, 1H), 8.05 (br. d,
1H, J = 7.6 Hz), 7.54-7.49 (m, 3H), 7.23 (br. s, 1H), 6.99 (br. s,
1H), 6.03 (br. s, 1H), 5.36 (m, 2H), 4.90 (m, 1H), 4.49 (dd, 1H, J
= 2.9 Hz, J = 9.0 Hz), 4.24 (m, 1H), 3.78 (s, 3H), 2.24 (m, 3H),
2.07 (m, 1H). "A103" ##STR00120##
6-[(R)-2-(2-Benzothiazol-2-ylphenoxymethyl)-
pyrrolidin-1-yl]-9H-purine 165-166 1.903 min [429.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.98 (br. s, 1H), 8.44 (dd,
1H, J = 1.5 Hz, J = 7.8 Hz), 8.27 (s, 1H), 8.13 (m, 2H), 8.07 (d,
1H, J = 8.1 Hz), 7.55 (ddd, 1H, J = 1.1 Hz, J = 7.3 Hz, J = 9.3
Hz), 7.52 (m 2H), 7.45 (ddd, 1H, J = 1.0 Hz, J = 7.3 Hz, J = (8.0
Hz), 7.17 (ddd, 1H, J = 1.3 Hz, J = 6.6 Hz, J = 7.9 Hz), 5.51 (br.
m, 1H), 4.95 (br. m, 1H), 4.68 (dd, 1H, J = 3.4 Hz, J = 9.1 Hz),
4.25 (t, 1H, J = 9.1 Hz), 3.84 (br. m 1H), 2.21 (m, 3H), 2.05 (m,
1H). "A104" ##STR00121##
6-[(R)-2-(Imidazo[1,2-a]pyridin-8-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine 115-117 1.105 min [336.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s, 1H), 8.24 (s,
1H), 8.12 (m, 2H), 7.91 (s, 1H), 7.48 (s, 1H), 6.73 (m, 2H), 5.36
(br. m, 1H), 4.82 (br. m, 1H), 4.47 (br. d, 1H, J = 8.5 Hz), 4.26
(dd, 1H, J = 7.8 Hz, J = 9.1 Hz), 3.76 (br. m, 1H), 2.31 (m 1H),
2.14 (m, 2H), 2.02 (m, 1H). "A105" ##STR00122##
6-Chloro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-2-trifluoromethylquinoline 230-231 1.955 min [449.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.02 (br. s,
1H), 8.25 (s, 1H), 8.11 (m, 3H), 7.98 (dd, 1H, J = 2.0 Hz, J = 9.0
Hz), 7.81 (m, 1H), 5.53 (br. m, 1H), 4.94 (br. m, 1H), 4.75 (dd,
1H, J = 4.4 Hz, J = 10.1 Hz), 4.47 (dd. 1H, J = 7.9 Hz, J = 10.1
Hz), 3.99 (m, 1H), 2.19 (m 3H), 2.07 (m, 1H). "A106" ##STR00123##
6-{(R)-2-[7-(4-Benzylpiperazin-1-yl)naphthalen-
1-yloxymethyl]pyrrolidin-1-yI}-9H-purine 78-80 1.687 min [520.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.94 (br. s,
1H), 8.22 (s, 1H), 8.08 (br. s, 1H), 7.69 (d, 1H, J = 9.1 Hz),
7.37-7.29 (m, 8H), 7.15 (t, 1H, J = 7.6 Hz), 6.95 (br. s, 1H), 5.47
(br. m, 1H), 4.89 (m 1H), 4.43 (br. dd, 1H, J = 2.2 Hz, J = 9.3
Hz), 4.20 (br. m, 1H), 3.84 (br. m, 1H), 3.21 (m, 4H), 2.58 (m,
4H), 2.25 (br. m, 3H), 2.06 (br. m, 1H). "A107" ##STR00124##
6-Dimethylamino-4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalene-2-sulfonic acid 1.173 min
[469.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.93 (br.
s, 1H), 8.63 (br. s, 1H), 8.58 (s, 1H), 8.19 (d, 1H, J = 9.0 Hz),
7.90 (d, 1H, J = 6.0 Hz), 7.87 (d, 1H, J = 6.0 Hz), 7.47 (s, 1H),
5.69-5.03 (br. m, 1H), 4.66 (m, 1H), 4.38 (m, 1H), 4.13-4.03 (m,
1H), 3.85 (br. m, 1H), 3.32 (s, 6H), 2.6 (br. m, 4H). "A108"
##STR00125## Naphthalen-1-yl[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethyl]amine 1.721 min [345.2] "A109" ##STR00126##
1-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl- methoxy]isoquinoline
201-202 1.656 min [347.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.94 (br. s, 1H), 8.20 (s, 1H), 8.09 (s, 2H), 7.92
(d, 1H, J = 5.6 Hz), 7.88 (d, 1H, 8.1 Hz), 7.76 (ddd, 1H, J = 1.1
Hz, J = 7.1 Hz, J = 8.1 Hz), 7.62 (t, 1H, J = 7.5 Hz), 7.35 (d, 1H,
J = 5.8 Hz), 5.21 (br. m, 1H), 4.72 (dd, 1H, J = 3.8 Hz, J = 10.5
Hz), 4.67 (dd, 1H, J = 6.3 Hz, J = 10.5 Hz), 3.97 (br. m, 2H), 2.22
(br. m, 3H), 2.05 (br. m, 1H). "A110" ##STR00127##
6-{(R)-2-[4-(4-Propylpiperazin-1-ylmethyl)-
naphthalen-1-yloxymethyl]pyrrolidin-1-yl}-9H-purine 145-147 1.370
min [486.4] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.24
(s, 1H), 8.20 (d, 1H, J = 8.5 Hz), 8.15 (d, 1H, J = 6.7 Hz), 8.10
(s, 1H),7.55 (t, 1H, J = 7.1 Hz),
7.50 (t, 1H, J = 7.1 Hz), 7.24 (d, 1H, J = 7.8 Hz), 5.13 (br. m,
1H), 4.49 (dd, 1H, J = 2.9 Hz, J = 8.9 Hz), 4.25 (t, 1H, J = 8.0
Hz), 3.98 (br. m, 2H), 3.74 (s, 2H), 3.38 (m, H), 2.39 (br. m, 4H),
2.26 (br. m, 6H), 2.17 (t, 3H, J = 7.2 Hz), 2.07 (br. m, 1H), 1.39
(hex, 2H, J = 7.3 Hz), 1.10 (t, 2H, J = 6.9 Hz), 0.83 (t, 3H, J =
7.3 Hz). "A111" ##STR00128##
1-(4-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}piperazin-1-yl)-ethanone 150-152
1.370 min [486.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
12.97 (br. s, 1H), 8.25 (s, 1H), 8.23 (d, 1H, J = 8.5 Hz), 8.16
(br. s, 1H), 8.12 (s, 1H), 7.56 (ddd, 1H, J = 1.2 Hz, J = 7.0 Hz, J
= 8.0 Hz), 7.51 (t, 1H, J = 7.0 Hz), 7.29 (d, 1H, J = 7.7 Hz), 6.99
(br. s, 1H), 5.19 (br. m, 1H), 4.50 (dd, 1H, J = 3.2 Hz, J = 9.3
Hz), 4.26 (t, 1H, J = 8.1 Hz), 4.16 (br. m, 1H), 3.78 (d, 2H, J =
2.1 Hz), 3.61 (m, 3H), 3.36 (m, 5H), 2.40 (m, 2H), 2.33 (m, 2H),
2.24 (br. m, 3H), 2.08 (br. m, 1H), 1.97 (s, 3H), 1.77 (m, 3H).
"A112" ##STR00129## 6-{(R)-2-[4-(4-Cyclopentylpiperazin-1-yl-
methyl)naphthalen-1-yloxymethyl]pyrrolidin-1- yl}-9H-purine 170-172
1.381 min [512.4] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
12.98 (br. s, 1H), 8.24 (s, 1H), 8.20 (d, 1H, J = 8.5 Hz), 8.14
(br. s, 1H), 8.11 (s, 1H), 7.55 (m, 1H), 7.50 (m, 1H), 7.27 (d, 1H,
J = 7.6 Hz), 6.97 (br. s, 1H), 4.91 (br. m, 1H), 4.49 (dd, 1H, J =
3.2 Hz, J = 9.2 Hz), 4.25 (t, 1H, J = 8.2 Hz), 3.99 (br. m, 2H),
3.73 (s, 2H), 3.61 (m, 2H), 2.39 (m, 8H), 2.24 (m, 4H), 2.07 (m,
1H), 1.77 (m, 2H), 1.72 (m, 2H), 1.58 (m, 2H), 1.46 (m, 2H), 1.28
(m, 2H). "A113" ##STR00130##
6-((R)-2-{4-[4-(2-Methoxyethyl)piperazin-1-yl-
methyl]naphthalen-1-yloxymethyl}pyrrolidin-1-yl)-9H-purine 210-212
1.363 min [502.2] "A114" ##STR00131##
((R)-1-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}pyrrolidin-2-yl)-methanol 137-139
1.378 min [459.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
12.97 (br. s, 1H), 8.30 (dd, 1H, J = 0.9 Hz, J = 8.3 Hz), 8.25 (s,
1H), 8.14 (br. m, 1H), 8.12 (s, 1H), 7.52 (m, 2H), 7.31 (d, 1H, 8.3
Hz), 6.96 (br. m, 1H), 5.19 (br. m, 1H), 4.48 (m, 3H), 4.24 (m,
1H), 4.08 (m, 1H), 3.83 (br. m, 1H), 3.54 (d, 1H, J = 12.5 hz),
3.49 (dd, 1H, J = 4.3 Hz, J = 9.9 Hz), 3.18 (s, 1H), 2.62 (m, 2H),
2.22 (m, 4H), 2.07 (m, 1H), 1.87 (m, 1H), 1.56 (m, 3H). "A115"
##STR00132## 6-[(R)-2-(7-Piperazin-1-ylnaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 100-101 1.485 min [430.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.23 (s, 1H),
8.11 (s, 1H), 7.69 (d, 1H, J = 9.1 Hz), 7.33 (dd, 1H, J = 2.4 Hz, J
= 9.0 Hz), 7.30 (m. 2H), 7.13 (t, 1H, J = 7.8 Hz), 6.94 (br. s,
1H), 5.21 (br. m, 1H), 4.43 (dd, 1H, J = 3.3 Hz, J = 9.3 Hz), 4.33
(dd, 1H, J = 6.4 Hz, J = 9.3 Hz), 4.06 (m, 2H), 3.09 (m, 4H), 2.89
(m, 4H), 2.31 (m, 1H), 2.23 (m, 2H), 2.08 (m, 1H). "A116"
##STR00133## 1-(4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazin-1-yl)- ethanone 131.5-133 1.685
min [472.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96
(br. s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.72 (d, 1H, J = 9.1 Hz),
7.38 (m, 1H), 7.33 (m, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 6.98 (m,
1H), 5.21 (br. m, 1H), 4.44 (dd, 1H, J = 3.0 Hz, J = 9.1 Hz), 4.31
(m, 1H), 3.87 (br. m, 2H), 3.64 (m, 3H), 3.59 (m, 2H), 3.18 (m,
4H), 2.29 (m, 2H), 2.22 (m, 2H), 2.08 (s, 3H). "A117" ##STR00134##
6-Methyl-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-2-trifluoromethylquinoline 245-246 1.869 min [429.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 13.02 (br. s,
1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, J = 8.6 Hz), 7.87
(br. s, 1H), 7.72 (dd, 2H, J = 1.5 Hz, J = 8.5 Hz), 5.26 (br. m,
1H), 4.72 (dd, 1H, J = 4.1 Hz, J = 10.0 Hz), 4.45 (dd, 1H, J = 8.1
Hz, J = 10.0 Hz), 4.26 (br. m, 1H), 3.82 (br. m, 1H), 2.53 (s, 3H),
2.20 (br. m, 3H), 2.07 (br. m, 1H). "A118" ##STR00135##
6-[(R)-2-(7-Methoxynaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine 140-141.5 1.830 min [376.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s, 1H), 8.25 (s,
1H), 8.12 (s, 1H), 7.78 (d, 1H, J = 8.9 Hz), 7.42 (br. s, 1H), 7.39
(d, 1H, J = 8.1 Hz), 7.23 (br. t, 1H, J = 7.8 Hz), 7.17 (dd, 1H, J
= 2.6 Hz, J = 8.9 Hz), 7.04 (br. s, 1H), 5.21 (br. m, 1H), 4.49
(dd, 1H, J = 2.9 Hz, J = 9.2 Hz), 4.32 (dd, 1H, J = 6.9 Hz, J = 9.2
Hz), 4.19 (br. m, 1H), 3.85 (s, 3H), 2.26 (br. m, 3H), 2.08 (br. m,
1H). "A119" ##STR00136##
6-[(R)-2-(7-Butoxy-5,6-dihydronaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 92-94 2.207 min [420.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.94 (br. s,
1H), 8.21 (s, 1H), 8.09 (s, 1H), 6.87 (m, 1H), 6.80 (br. m, 1H),
6.66 (d, 1H, J = 7.3 Hz), 5.74 (s, 1H), 5.03 (br. m, 1H), 4.24 (m,
1H), 4.14 (m, 1H), 3.76 (m, 2H), 3.42 (m, 1H), 2.74 (m, 2H), 2.69
(m, 1H), 2.26 (m, 2H), 2.16 (br. m, 3H), 2.02 (br. m, 1H), 1.67 (m,
2H), 1.37 (m, 2H), 0.82 (t, 3H, J = 7.3 Hz). "A120" ##STR00137##
Benzyl 8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate 88-90 1.957 min
[485.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.59
(br. s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.40 (m, 4H), 7.34 (m,
1H), 7.11 (t, 1H, J = 7.5 Hz), 6.91 (br. m, 1H), 6.74 (d, 1H, J =
7.5 Hz), 5.14 (s, 2H), 4.74 (br. m, 1H), 4.50 (m, 2H), 4.32 (m,
1H), 4.15 (m, 1H), 3.74 (m, 1H), 3.61 (m, 2H), 2.76 (m, 2H), 2.11
(br. m, 3H), 1.91 (br. m, 1H). "A121" ##STR00138##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
3,4-dihydro-1H-naphthalen-2-one 140.5-142 1.590 min [364.2] .sup.1H
NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.97 (br. s, 1H), 8.22
(s, 1H), 8.10 (s, 1H), 7.12 (t, 1H, J = 7.6 Hz), 6.93 (br. m, 1H),
6.84 (d, 1H, J = 7.6 Hz), 5.05 (br. m, 1H), 4.30 (dd, 1H, J = 3.3
Hz, J = 9.3 Hz), 4.08 (dd, 1H, J = 6.6 Hz, J = 9.3 Hz), 3.76 (br.
m, 4H), 2.99 (m, 2H), 2.46 (dd, 2H, J = 5.8 Hz, J = 7.7 Hz), 2.15
(br. m, 3H), 2.03 (br. m, 1H). "A122" ##STR00139##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
1,2,3,4-tetrahydroisoquinoline 85-87 1.231 min [351.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 8.23 (s, 1H), 8.11 (s, 1H),
7.01 (br. t, 1H, J = 7.7 Hz), 6.78 (br. m, 1H), 6.64 (d, 1H, J =
7.7 Hz), 5.02 (br. m, 1H), 4.27 (dd, 1H, J = 2.8, J = 9.1 Hz), 4.09
(dd, 1H, J = 6.9 Hz, J = 9.1 Hz), 3.67 (m, 2H), 3.38 (m, 2H), 2.88
(m, 2H), 2.63 (m, 2H), 2.15 (br. m, 3H), 2.02 (br. m 1H). "A123"
##STR00140## 4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
6-trifluoromethylquinoline 139-140 1.380 min [415.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.98 (br. s, 1H), 8.88 (d,
1H, J = 5.2 Hz), 8.36 (br. s, 1H), 8.26 (s, 1H), 8.15 (d, 1H, J =
8.8 Hz), 8.13 (s, 1H), 7.99 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz), 7.39
(br. s, 1H), 5.26 (br. m, 1H), 4.65 (dd, 1H, J = 4.2 Hz, J = 9.7
Hz), 4.42 (dd, 1H, J = 7.3 Hz, J = 9.7 Hz), 3.93 (br. m, 2H), 2.21
(br. m, 3H), 2.08 (br. m, 1H). "A124" ##STR00141##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl- methoxy]naphthalen-2-ol
146.5-148 1.648 min [362.2] .sup.1H NMR (500 MHz, d.sub.6-DMSO)
.delta. [ppm] 12.96 (br. s, 1H), 9.74 (br. s, 1H), 8.24 (s, 1H),
8.12 (s, 1H), 7.70 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 2.3 Hz),
7.33 (d, 1H, J = 8.2 Hz), 7.12 (br. t, 1H, J = 7.7 Hz), 7.07 (dd,
1H, J = 2.4 Hz, J = 8.8 Hz), 6.93 (br. s, 1H), 5.15 (br. m, 1H),
4.46 (dd, 1H, J = 1.9 Hz, J = 9.1 Hz), 4.24 (dd, 1H, J = 7.6 Hz, J
= 9.1 Hz), 3.85 (br. m, 2H), 2.25 (br. m, 3H), 2.08 (br. m, 1H).
"A125" ##STR00142## (S)-2-(4-Chloro-2-methyl-2H-pyrazol-3-yl-
methyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-2H-naphthalen-1-one "A126" ##STR00143##
(R)-2-(4-Chloro-2-methyl-2H-pyrazol-3-yl-
methyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-2H-naphthalen-1-one "A127" ##STR00144##
N,N-Diethyl-3-hydroxy-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalene-2-carboxamide 1.643 min [461.2]
.sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.96 (br. s,
1H), 10.04 (br. s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.61 (s, 1H),
7.54 (s, 1H), 7.30 (d, 1H, J = 8.1 Hz), 7.17 (t, 1H, J = 7.7 Hz),
6.85 (d, 1H, J = 7.5 Hz), 5.03 (br. m, 1H), 4.46 (m, 1H), 4.28 (m,
2H), 3.91 (m, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.14 (m, 1H), 3.00
(m, 1H), 2.13 (m, 3H), 1.98 (m, 1H), 1.20 (m, 4), 1.00 (m, 2H).
"A128" ##STR00145## 3-(4-{4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ylmethyl}piperazin-1-yl)-propionitrile 1.399
min [497.2] "A129" ##STR00146##
(R)-5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-2-(1H-pyrazol-3-ylmethyl)-3,4-dihydro- 2H-naphthalen-1-one
"A130" ##STR00147## (S)-5-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-2-(1H-pyrazol-3-ylmethyl)-3,4-dihydro- 2H-naphthalen-1-one
"A131" ##STR00148##
8-{[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethyl]-
amino}naphthalen-2-ol .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta.
[ppm] 12.97 (br. s, 1H), 9.41 (s, 1H), 8.37 (br, s. 1H), 8.13 (br.
s, 1H), 7.59 (d, 1H, J = 8.7 Hz), 7.29 (br. s, 1H), 7.08 (dd, 1H, J
= 7.5 Hz, J = 7.9 Hz), 7.02 (dd, 1H, J = 2.2 Hz, J = 8.7 Hz), 6.99
(d, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 7.5 Hz), 6.33 (br, m, 1H),
4.86 (br, m, 1H), 4.18 (br. m, 1H), 3.61 (m, 1H), 3.18 (m, 1H),
2.13 (m, 2H), 1.99 (m, 2H). "A132" ##STR00149##
8-{[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yimethyl]-
amino}naphthalene-2-sulfonic acid .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. [ppm] 8.58 (br. s, 1H), 8.43 (s, 1H), 8.09
(br. s, 1H), 7.67 (d, 1H, J = 8.5 Hz), 7.63 (dd, 1H, J = 1.2 Hz, J
= 8.5 Hz), 7.30 (t, 1H, J = 7.8 Hz), 7.15 (br. s, 1H), 7.05 (d, 1H,
J = 8.1 Hz), 6.99 (d, 1H, J = 7.7 Hz), 4.86 (br. m, 1H), 4.19 (br.
m, 1H), 3.77 (br. m, 1H), 3.62 (m, 1H), 2.97 (m, 1H), 2.14 (m, 2H),
2.01 (m, 2H). "A133" ##STR00150## tert-Butyl
(6-oxo-6-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-
isoquinolin-2-yl}hexyl)carbamate 82-83.5 2.039 min
[564.3].sup..sctn. "A134" ##STR00151##
3-(2-{6-[(R)-2-(7-Hydroxynaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]purin-9-yl}ethyl)- dihydrofuran-2-one
2.012 min [474.2] .sup..sctn. "A135" ##STR00152##
3-{6-[(R)-2-(7-Hydroxynaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]purin-9-yl}-propionamide 1.737 min
[433.2] .sup..sctn. "A136" ##STR00153## Ethyl
5-{6-[(R)-2-(7-hydroxynaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]purin-9-yl}pentanoate 2.190 min [490.2]
.sup..sctn. "A137" ##STR00154##
4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylmethoxy]-
6-trifluoromethoxyquinoline 111-112 1.443 min [431.2] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.98 (br. s, 1H), 8.77 (d,
1H, J = 5.1 Hz), 8.25 (s, 1H), 8.12 (s, 1H), 8.08 (d, 1H, J = 9.1
Hz), 7.89 (br. m, 1H), 7.73 (dd, 1H, J = 2.5 Hz, J = 9.1 Hz), 7.29
(br. m, 1H), 5.16 (br. m, 1H), 4.62 (dd, 1H, J = 3.8 Hz, J = 9.7
Hz), 4.41 (dd, 1H, J = 7.4 Hz, J = 9.7 Hz), 3.93 (br. m, 2H), 2.20
(br. m, 3H), 2.07 (br. m, 1H). "A138" ##STR00155##
6-Amino-1-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-
ylmethoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-hexan-1-one 76-78 1.372
min [464.3] .sup..sctn. "A139" ##STR00156## Butyl
6-fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]quinoline-2-carboxylate 108-109 2.154 min [465.2]
.sup..sctn. "A140" ##STR00157##
6-Fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-2-trifluoromethylquinoline 1-oxide 232-233 2.303 min
[449.1] .sup..sctn. "A141" ##STR00158##
6-Fluoro-4-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]quinoline-2-carboxylic acid 197-198 1.382 min [409.1]
.sup..sctn.
"A142" ##STR00159## 6-[(R)-2-(7-Nitronaphthalen-1-yloxymethyl)-
pyrrolidin-1-yl]-9H-purine 2.020 min [391.1] .sup..sctn. "A143"
##STR00160## (R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethyl 2-
methylaminobenzoate 1.809 min [353.2] "A144" ##STR00161##
8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-ylamine "A145" ##STR00162##
6-{(R)-2-[7-(4-Methylpiperazin-1-yl)naphthalen-
1-yloxymethyl]pyrrolidin-1-yl}-9H-purine 108-110 1.439
min.sup..sctn. [442.2] "A146" ##STR00163##
6-[(R)-2-(7-Morpholin-4-ylnaphthalen-1-yl-
oxymethyl)pyrrolidin-1-yl]-9H-purine 210-211 1.917 min.sup.$
[431.2] "A147" ##STR00164##
4-[(R)-1-(8-Fluoro-9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-1-ol 110-112 2.434 min.sup.$ [380.1] "A148"
##STR00165## 4-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]isoquinoline 157-158.5 1.318 min.sup.$ [347.1] .sup.1H NMR
(500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.86 (br. s, 1H), 8.92 (s,
1H), 8.23 (s, 2H), 8.09 (m, 3H), 7.78 (ddd, 1H, J = 0.9 Hz, J = 7.0
Hz, J = 8.0 Hz), 5.12 (br. m, 1H), 4.60 (dd, 1H, J = 3.4 Hz, J =
9.3 Hz), 2.55 (br. m, 2H), 2.23 (m, 3H), 2.06 (m, 1H). "A149"
##STR00166## N-(2-Morpholin-4-ylethyl)-4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide 136-138 2.32**
1.299 min.sup.$ [503.3] "A150" ##STR00167##
N-(3-Morpholin-4-ylpropyl)-4-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]quinoline-2-carboxamide 173-174 2.37**
1.356 min.sup.$ [517.3] "A151" ##STR00168## Methyl
5-fluoro-1-methyl-3-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylate 170-171 1.975
min.sup.$ [425.1] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm]
12.94 (br. s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.59 (dd, 1H, J =
4.3 Hz, J = 9.2 Hz), 7.49 (dd, 1H, J = 2.5 Hz, J = 9.2 Hz), 7.22
(dt, 1H, J = 2.5 Hz, J = 9.2 Hz), 5.13 (br. m, 1H), 4.56 (m, 2H),
4.20 (br. m, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 2.16 (m, 3H), 1.97
(br. m, 1H). "A152" ##STR00169##
N,N-Dimethyl-3-[2-(4-methoxyphenyl)ethoxy]-8-
[2-(4-methoxyphenyl)ethyl]-5-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]naphthalene-2-carboxamide "A153"
##STR00170## 6-{(R)-2-[1-(2,4-Dichlorophenyl)-1H-pyrazol-3-
yloxymethyl]pyrrolidin-1-yl}-9H-purine 147-149 1.988 min.sup.$
[430.1] .sup.1H NMR (500 MHz, d.sub.6-DMSO) .delta. [ppm] 12.95
(br. s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 8.00 (br. s, 1H), 7.82 (d,
1H, J = 1.2 Hz), 7.63 (s, 1H), 7.54 (m, 2H), 4.73 (br. m, 1H), 4.26
(br. m, 1H), 3.99 (t, 1H, J = 8.8 Hz), 3.67 (br. m, 2H), 2.10 (br.
m, 3H), 1.99 (br. m, 1H). "A154" ##STR00171##
1-Ethyl-3-{8-[(R)-1-(9H-purin-6-yi)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}urea 160-162 1.702 min.sup.$ [432.2] "A155"
##STR00172## N-Ethyl-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazine-1-carboxamide 141.5-143 1.840
min.sup.$ [501.3] "A156" ##STR00173##
N-(Furan-2-ylmethyl)-4-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl}- piperazine-1-carboxamide
136-137 1.974 min.sup.$ [553.3] "A157" ##STR00174## Ethyl
[(4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazine-1- carbonyl)amino]acetate
130-131 1.881 min.sup.$ [559.3] "A158" ##STR00175##
[(4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl}piperazine-1- carbonyl)amino]acetic acid
210 1.748 min.sup.$ [531.3] "A159" ##STR00176##
1-Furan-2-ylmethyl-3-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl}urea 141-143 1.981 min.sup.$
[484.2] "A160" ##STR00177## Methyl
(S)-4-benzyloxycarbonylamino-4-{8-[(R)-
1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
naphthalen-2-ylcarbamoyl}butyrate 122-124 "A161" ##STR00178##
tert-Butyl ((S)-3-carbamoyl-1-{8-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalen-2-
ylcarbamoyl}propyl)carbamate 146-148 1.867 min.sup.$ [589.3] "A162"
##STR00179## tert-Butyl ((R)-2-carbamoyl-1-{8-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]naphthalen-2-
ylcarbamoyl}ethyl)carbamate 157-160 1.864 min.sup.$ [575.3] "A163"
##STR00180## tert-Butyl ((S)-2-(1H-imidazol-4-yl)-1-{8-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
naphthalen-2-ylcarbamoyl}ethyl)carbamate 181-182 1.793 min.sup.$
[598.3] "A164" ##STR00181##
(S)-2-Amino-3-(1H-imidazol-4-yl)-N-{8-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
naphthalen-2-yl}propionamide * HCl 210 (decomp.) 1.333 min [498.2]
"A165" ##STR00182## N-(1-({8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yl})-(S)-2-aminopentan- 5-amide * HCl 210-212
1.441 min.sup.$ [489.2] "A166" ##STR00183##
4-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-ylm-
ethoxy]naphthalen-2-yl}piperazine-1-carbaldehyde 134-135 1.829
min.sup.$ [458.2] "A167" ##STR00184## tert-Butyl
[2-oxo-2-(4-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl}-
piperazin-1-yl)ethyl]carbamate 140-141 2.150 min.sup.$ [587.3]
"A168" ##STR00185##
2-Amino-1-(4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-
2-ylmethoxy]naphthalen-2-yl}piperazin-1-yl)-ethanone 247-249 1.546
min.sup.$ [487.3] "A169" ##STR00186##
1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2- yl}pyrrolidin-3-ol 73-75
1.370 min.sup.$ [435.3] "A170" ##STR00187##
1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2- yl}azetidin-3-ol 295-297
1.359 min.sup.$ [421.2] "A171" ##STR00188##
N-(1-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-1,2,3,4-tetrahydronaphthalen-2-
yl}pyrrolidin-3-yl)acetamide 163-164.5 1.398 min.sup.$ [476.3]
"A172" ##STR00189##
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]isoquinolin-1-yl}amine 87-88 1.295 min.sup.$
[475.2] "A173" ##STR00190##
N,N-Dimethyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide 78-81.5 1.657 min.sup.$ [449.2] "A174"
##STR00191## N,N-Dimethyl-2-{(S)-1-oxo-5-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide "A175" ##STR00192##
N,N-Dimethyl-2-{(R)-1-oxo-5-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide "A176" ##STR00193##
N-Ethyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide 93-95 1.613 min.sup.$ [449.2] "A177"
##STR00194## (R)-2-Amino-N1-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl}succinamide "A178"
##STR00195## (3-Morpholin-4-ylpropyl)-{4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]isoquinolin-1-yl}amine 73-75 1.222
min.sup.$ [489.3] "A179" ##STR00196##
N-Methyl-2-{1-oxo-5-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide 97-98 1.551 min.sup.$ [435.2] "A180"
##STR00197## N-(2-Hydroxyethyl)-2-{1-oxo-5-[(R)-1-(9H-purin-
6-yl)pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-
naphthalen-2-yl}acetamide 101-103 1.474 min.sup.$ [465.2] "A181"
##STR00198## N,N-Dimethyl-N'-{4-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]isoquinolin-1-yl}ethane- 1,2-diamine 63-65
1.261 min.sup.$ [433.2] "A182" ##STR00199##
N,N-Dimethyl-N'{(R)-1-9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]isoquinolin-1-yl}propane- 1,3-diamine 74-75
1.255 min.sup.$ [447.2] "A183" ##STR00200##
(S)-4-Carboxyamino-4-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]naphthalen-2-yl- carbamoyl}butyric acid
176-178 1.653 min.sup.$ [534.2] "A184" ##STR00201## Ethyl
5-fIuoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylate 132-134 2.095
min.sup.$ [439.2] "A185" ##STR00202## Ethyl
1-ethoxycarbonylmethyl-5-fluoro-3-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylate
178-180 2.- 110 min.sup.$ [511.2] "A186" ##STR00203##
3-(2-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yloxy}ethyl)dihydrofuran-2-one 2.075 min.sup.$
[474.2] "A187" ##STR00204## tert-Butyl
((S)-3-carbamoyl-1-{8-[(R)-1-(9H-
purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-
1H-isoquinoline-2-carbonyl}propyl)carbamate 78-80 1.737 min.sup.$
[579.3] "A188" ##STR00205## tert-Butyl
((R)-1-carbamoylmethyl-2-oxo-2-{8-
[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-
3,4-dihydro-1H-isoquinolin-2-yl}ethyl)carbamate 82-83.5 1.738
min.sup.$ [565.3] "A189" ##STR00206## tert-Butyl
((S)-1-(1H-imidazol-4-ylmethyl)-2-oxo-
2-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}ethyl)- carbamate 93-95
1.587 min.sup.$ [588.3] "A190" ##STR00207##
5-Fluoro-1-methyl-3-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-1H-indole-2-carboxylic acid 1.750 min.sup.$
[411.1] "A191" ##STR00208##
(2-Morpholin-4-ylethyl)-{4-[(R)-1-(9H-purin-6-
yl)pyrrolidin-2-ylmethoxy]quinolin-2-yl-methyl}amine 1.339
min.sup.$ [489.2] "A192" ##STR00209##
(S)-5-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinoline-2- carbonyl}pyrrolidin-2-one
112-113 1.565 min.sup.$ [462.2] "A193" ##STR00210## tert-Butyl
((S)-5-benzyloxycarbonylamino-6-oxo-
6-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}hexyl)-carbamate 94-96
2.305 min.sup.$ [713.4] "A194" ##STR00211##
(R)-3-Amino-4-oxo-4-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H- isoquinolin-2-yl}butyramide
123-124 1.295 min.sup.$ [465.3] "A195" ##STR00212##
(S)-2-Amino-3-(1H-imidazol-4-yl)-1-{8-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-
dihydro-1H-isoquinolin-2-yl}propan-1-one 93-94 1.194 min.sup.$
[488.2] "A196" ##STR00213##
5-{8-[(R)-1-(9H-Purin-6-yl)pyrrolidin-2-yl-
methoxy]naphthalen-2-yloxy}pentanoic acid >299 2.024 min.sup.$
[462.2] "A197" ##STR00214##
N-(4-Fluorobenzyl)-5-fluoro-1-methyl-3-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-1H- indole-2-carboxamide
135-137 2.274 min [518.2] "A198" ##STR00215##
2-(4-Fluorophenyl)ethyl 5-fluoro-1-methyl-3-
[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-1H-
indole-2-carboxylate 197-199 2.339 min.sup.$ [532.2] "A199"
##STR00216## Benzyl ((S)-5-amino-1-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H-
isoquinolin-2-carbonyl}pentyl)carbamate 104-106 1.667 min.sup.$
[613.3] "A200" ##STR00217##
N-[2-(4-Fluorophenyl)ethyl]-5-fluoro-1-{[2-(4-
fluorophenyl)ethylcarbamoyl]methyl}-3-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-1H- indole-2-carboxamide
2.403 min.sup.$ [697.3] "A201" ##STR00218##
(S)-3-Amino-4-oxo-4-{8-[(R)-1-(9H-purin-6-yl)-
pyrrolidin-2-ylmethoxy]-3,4-dihydro-1H- isoquinolin-2-yl}butyramide
103-104.5 1.290 min.sup.$ [465.2] "A202" ##STR00219##
4-Oxo-4-{8-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-yl-
methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-butyramide 102-104 1.527
min.sup.$ [450.2] "A203" ##STR00220##
[2-(4-Fluorophenyl)ethyl]-(2-{5-fluoro-3-[(R)-1-
(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]indol-1-yl}-ethyl)amine 89-91
2.155 min.sup.$ [518.2]
TABLE-US-00003 TABLE 1 Inhibition of MetAP-2 IC.sub.50 of compounds
according to the invention Compound No. IC.sub.50 enzyme "A1" A
"A2" A "A3" A "A4" A "A5" B "A6" "A7" B "A8" B "A9" "A10" "A11" B
"A12" B "A13" B "A14" B "A15" A "A16" C "A17" C "A18" C "A19" "A20"
"A21" C "A22" C "A23" C "A24" C "A25" B "A26" C "A27" C "A28" B
"A29" "A30" C "A31" "A32" C "A33" C "A34" C "A35" "A36" "A37" B
"A38" A "A39" B "A40" B "A41" A "A42" B "A43" B "A44" A "A45" C
"A46" C "A47" B "A48" A "A49" B "A50" A "A51" A "A52" "A53" A "A54"
"A55" A "A56" B "A57" A "A58" A "A59" C "A60" A "A61" C "A62" B
"A63" B "A64" C "A65" A "A66" A "A67" A "A68" A "A69" B "A70" A
"A71" A "A72" B "A73" B "A74" A "A75" B "A76" C "A77" B "A78" B
"A79" A "A80" A "A81" A "A82" A "A83" A "A84" A "A85" A "A86" A
"A87" A "A88" A "A89" A "A90" B "A91" B "A92" A "A93" A "A94" A
"A95" A "A96" A "A97" A "A98" A "A99" A "A100" A "A101" A "A102" A
"A103" B "A104" B "A105" A "A106" C "A107" B "A108" C "A109" A
"A110" A "A111" A "A112" A "A113" A "A114" A "A115" A "A116" A
"A117" A "A118" A "A119" B "A120" B "A121" B "A122" A "A123" A
"A124" B "A125" A "A126" A "A127" A "A128" A "A129" A "A130" A
"A131" C "A132" C "A133" B "A134" B "A135" C "A136" C "A137" A
"A138" A "A139" A "A140" A "A141" A "A142" A "A143" A "A144" A
"A145" B "A146" A "A147" B "A148" A "A149" C "A150" A "A151" A
"A152" C "A153" A "A154" B "A155" B "A156" B "A157" B "A158" C
"A159" B "A160" C "A161" B "A162" B "A163" B "A164" B "A165" B
"A166" A "A167" B "A168" B "A169" B "A170" A "A171" B "A172" B
"A173" A "A174" A "A175" A "A176" A "A177" B "A178" B "A179" A
"A180" A "A181" A "A182" A "A183" C "A184" C "A185" C "A186" B
"A187" B "A188" B "A189" B "A190" C "A191" A "A192" A "A193" C
"A194" A "A195" A "A196" C "A197" C "A198" C "A199" B "A200" C
"A201" B "A202" B "A203" C IC.sub.50: 10 nM-1 .mu.M = A 1 .mu.M-10
.mu.M = B >10 .mu.M = C
The following examples relate to medicaments:
Example A
Injection Vials
A solution of 100 g of an active ingredient of the formula I and 5
g of disodium hydrogenphosphate in 0.3 l of bidistilled water is
adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered,
transferred into injection vials, lyophilised under sterile
conditions and sealed under sterile conditions. Each injection vial
contains 0.5 mg of active ingredient.
Example B
Suppositories
A mixture of 20 g of an active ingredient of the formula I with 100
g of soya lecithin and 1400 g of cocoa butter is melted, poured
into moulds and allowed to cool. Each suppository contains 20 mg of
active ingredient.
EXAMPLE C
Solution
A solution is prepared from 1 g of an active ingredient of the
formula I, 9.38 g of NaH.sub.2PO.sub.4 2 H.sub.2O, 28.48 g of
Na.sub.2HPO.sub.4 12 H.sub.2O and 0.1 g of benzalkonium chloride in
940 ml of bidistilled water. The pH is adjusted to 6.8, and the
solution is made up to 1 l and sterilised by irradiation. This
solution can be used in the form of eye drops.
Example D
Ointment
500 mg of an active ingredient of the formula I are mixed with 99.5
g of Vaseline under aseptic conditions.
Example E
Tablets
A mixture of 1 kg of active ingredient of the formula I, 4 kg of
lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of
magnesium stearate is pressed in a conventional manner to give
tablets in such a way that each tablet contains 10 mg of active
ingredient.
Example F
Dragees
Tablets are pressed analogously to Example E and subsequently
coated in a conventional manner with a coating of sucrose, potato
starch, talc, tragacanth and dye.
Example G
Capsules
2 kg of active ingredient of the formula I are introduced into hard
gelatine capsules in a conventional manner in such a way that each
capsule contains 20 mg of the active ingredient.
Example H
Ampoules
A solution of 1 kg of active ingredient of the formula I in 60 l of
bidistilled water is sterile filtered, transferred into ampoules,
lyophilised under sterile conditions and sealed under sterile
conditions. Each ampoule contains 10 mg of active ingredient.
* * * * *
References